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Evidence supports severe renal insufficiency as a relative contraindication to heart transplantation
http://www.jhltonline.org
ORIGINAL CLINICAL SCIENCE
Evidence supports severe renal insufficiency as a relative contraindication to heart transplantation Kimberly N. Hong, MD, MHSA,a Aurelie Merlo, BA,b Dhaval Chauhan, MD,c,d Ryan R. Davies, MD,e Alexander Iribarne, MD,f Elizabeth Johnson, MA,g Val Jeevanandam, MD,g and Mark J. Russo, MD, MSc,d From the aDepartment of Cardiology, Mount Sinai School of Medicine, New York, New York; b Case Western Reserve Medical School, Cleveland, Ohio; cDepartment of Surgery, Rutgers–New Jersey Medical School, Newark, New Jersey; dCardiovascular Clinical Research Unit, Barnabas Heart Hospitals, Newark, New Jersey e Division of Pediatric Cardiothoracic Surgery, Nemours/Alfred I. DuPont Hospital for Children, Wilmington, Delaware; f Department of Cardiothoracic Surgery, Dartmouth Medical Center, Hanover, New Hampshire g Section of Cardiac and Thoracic Surgery, Department of Surgery, University of Chicago, Chicago, Illinois.
KEYWORDS: orthotopic heart transplant; outcomes; mortality; renal insufficiency; estimated glomerular filtration rate; chronic kidney disease
BACKGROUND: This study was conducted to determine whether survival after orthotopic heart transplant (OHT) is associated with pre-transplant estimated glomerular filtration rate (eGFR) and to define ranges of pre-OHT eGFR associated with differences in post-transplant survival. The 2006 International Society for Heart and Lung Transplantation revised listing criteria for OHT stated that chronic kidney disease, defined by an eGFR o40 ml/min is a relative contraindication for OHT alone. The committee noted that this recommendation was supported by consensus opinion of experts and not data derived from a randomized trial or non-randomized studies. METHODS: The United Network for Organ Sharing provided deidentified patient-level data. The study population included 17,459 OHT recipients aged Z18 years who received allografts between January 1, 2001, and December 31, 2009. Logistic regression was used to assess the effect of multiple variables on survival after OHT. Receiver operating characteristic curves and stratum-specific likelihood ratios were generated to compare 1-year survival at eGFR thresholds. The primary outcomes measure was actuarial post-transplant survival expressed in years. RESULTS: Regression analysis showed that a lower pre-transplant eGFR is associated with worse posttransplant survival. Threshold analysis demonstrated 3 distinct survival strata: eGFR r 34 ml/min, eGFR 35 to 49 ml/min, and eGFR 4 49 ml/min. Graft survival at all times is decreased for patients with eGFR r 34 ml/min. They are also more likely to have in-hospital and long-term complications. CONCLUSIONS: eGFR is a strong predictor of post-transplant survival and should be considered when assessing patients for OHT. This analysis supports current International Society for Heart and Lung Transplantation guidelines and suggests that end-stage heart failure patients with an eGFR r 34 ml/min is a relative contraindication for heart transplantation alone. J Heart Lung Transplant ]]]];]:]]]–]]] r 2016 International Society for Heart and Lung Transplantation. All rights reserved.
Reprint requests: Dhaval Chauhan, MD, Department of Surgery,185 South Orange Avenue, Medical Science Building, Suite G-538, Newark, NJ 07103. Telephone: þ1-631-627-9166. E-mail address: [email protected]
End-stage heart failure is a significant problem in the United States. Currently, more than 60,000 deaths per year are directly attributed to end-stage disease, and an additional 250,000 patients with advanced stages of heart failure die from related causes.1 Orthotopic heart transplantation
1053-2498/$ - see front matter r 2016 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2016.02.003
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(OHT) remains the gold standard in the treatment of endstage heart failure. Unfortunately, due to a critical scarcity of available organs for transplantation, in any given year, fewer than 2,500 potential beneficiaries undergo OHT.2 Therefore, achieving maximal benefit from this therapy is predicated on improved patient selection. To this end, revised listing criteria for OHT were published by the International Society for Heart and Lung Transplantation (ISHLT) in 2006.3 The current guidelines state that chronic kidney disease (CKD), defined by an estimated glomerular filtration rate (eGFR) o 40 ml/min, is a relative contraindication for OHT alone. CKD has a strong association with end-stage heart failure, and is therefore commonly seen in OHT candidates. However, this recommendation related to severity of kidney disease and a candidate’s appropriateness for transplantation was supported only by consensus opinion (Level C Evidence) and not by objective data (Level A or B Evidence). A better body of evidence is clearly needed to refine future guidelines. We therefore, we chose to analyze the United Network for Organ Sharing (UNOS) database in an attempt to objectively define risks facing OHT recipients with various degrees of kidney disease. The purposes of this study were to (1) define ranges of eGFR before OHT associated with differences in post-transplant survival and (2) to describe post-transplant outcomes within eGFR strata.
Methods Data collection Use of these data is consistent with the regulations of the University of Chicago’s Institutional Review Board. UNOS provided deidentified patient-level data from the Thoracic Registry (data source 01052011–6). These data include all OHT recipients and donors in the United States and reported to the Organ Procurement and Transplantation Network between January 1, 2001, and December 31, 2009. Data entry by all United States transplant centers is mandated by the 1984 National Transplantation Act. The eGFR was calculated from pre-OHT serum creatinine using the Modification of Diet in Renal Disease (MDRD) Study Equation. Chronic dialysis patients were assigned an eGFR of 10 ml/min.
complications. Measures of transplant hospitalization morbidity included incidence of stroke, infection, and need for hemodialysis (HD) during the transplant hospitalization. Long-term complications were assessed by time-to-event analysis where the events of interest include transplant coronary artery disease (TCAD), chronic HD, severe infection, and severe rejection. HD-dependent recipients at transplant were dropped from the chronic HD–free survival analysis.
Data analysis Continuous variables are reported as means ⫾ standard deviation and were compared by using the Student’s t-test. Categoric variables were compared with the chi-square test. The conventional p-value value of 0.05 was used to determine statistical significance. All reported p-values are 2 sided.
Survival and other time-to-event analysis Kaplan-Meier analysis was used to calculate actuarial eventfree survival. For survival analysis, the outcome of interest was death (4,771 [27.0%]) or re-transplantation (198 [1.1%]). Other patients, including those lost to follow-up (526 [3.0%]) or alive at last follow-up (11,964 [69.0%]), were censored on the day of last known follow-up. To assess the simultaneous effect of multiple variables on the graft survival after OHT, multivariable logistic regression analysis (backward, p o 0.15) was used to determine the relationship between groups and 1-year graft survival. Long-term complications, excluding renal failure, were reported as event-free survival, where the outcome of interest was the specified complication. A composite end point that included death, HD, or renal transplantation was used to evaluate time to CKD stage 5 requiring HD.
Threshold analysis Receiver operating characteristic (ROC) curves and stratumspecific likelihood ratios (SSLR) were used in the threshold analysis to define eGFR strata. Receiver-operating characteristic curves were generated (Figure 1) by plotting sensitivity on the ordinate and 1–specificity on the abscissa with eGFR as a
Study population The study population included 17,459 first-time OHT patients aged 18 years and older between January 1, 2001, and December 31, 2009. The analysis excluded 980 patients because of lack of data (n ¼ 484) or because they were multiorgan transplant recipients (n ¼ 496). Patients were monitored from the date of transplantation to January 3, 2011, which was the last day of follow-up provided by UNOS.
Outcome measures The primary outcomes measure was actuarial post-transplant graft survival. Other outcomes of interest included primary graft failure at 1 year, transplant hospitalization morbidity, and long-term
Figure 1 Receiver operating characteristic (ROC) curve shows the estimated glomerular filtration rate as a predictor of 1-year mortality.
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continuous variable and mortality at 1 year as a binary outcome.4,5 SSLRs and 95% confidence intervals were generated using data cutpoints at regular intervals, as previously described.6,7 Cutpoints, or threshold values, for eGFR were determined by combining adjacent GFR strata with other statistically indistinct strata based on the presence of SSLRs with overlapping 95% confidence intervals. Cutpoints occurred when 2 statistically distinct strata could be formed. This process was repeated until no additional cutpoints were found.
3 Table 2
Estimated Glomerular Filtration Rate Strata
Strata
No.
SSLR (95% CI)
eGFR r 34 ml/min eGFR 35–49 ml/min eGFR 4 49 ml/min
1323 2791 13,345
2.53 (2.26–2.84) 1.22 (1.11–1.34) 0.83 (0.80–0.85)
CI, confidence interval; eGFR, estimated glomerular filtration rate; SSLR, stratum-specific likelihood ratio.
Primary outcomes
Results Study population The study population included 17,459 first-time OHT recipients. Mean follow-up was 4.15 ⫾ 2.96 years (range, 0–11.09 years). Clinical characteristics of the study population are included in Table 1. Threshold analysis generated three separate eGFR strata (ml/min): eGFR r 34 (1,323 [7.6%]), eGFR 35 to 49 (2,791 [16.0%]), and eGFR 4 49 (13,345 [76.4%]; Table 2). Table 1
Post-transplant graft survival in the eGFR r 34 ml/min group is significantly worse than in the eGFR 35–49 ml/ min/ or eGFR 4 49 ml/min groups (p o 0.001), with median survival in the 3 groups at 8.2 years, 10.0 years, and 10.3 years, respectively. At 3 months, graft survival was 82.1%, 90.7%, and 94.0% in the eGFR r 34 ml/min, eGFR 35–49 ml/min, and eGFR 449 ml/min groups, respectively. This reduced graft survival persists at all post-transplant time points (Figure 2). Conditional 1-year survival is shown in Figure 3.
Patient Characteristics for all Heart Transplant Recipients Aged 18 Years and Older (2001–2009)
Variablea
eGFR r 34 ml/min eGFR 35–49 ml/min p-valueb eGFR 4 49 ml/min p-valueb Total
Heart transplant recipients Donor age, years Donor organ ischemic time, hours Cause of heart failure Ischemic Dilated Congenital Valvular Sarcoidosis Amyloidosis Life support at transplant IABP ECMO RVAD BVAD MCS EVAD MCS PVAD MCS implantable device Age, years Status 1 at transplant ICU at transplant Male sex Steroids Total bilirubin 4 2.0 mg/dl Diabetes mellitus Hypertensive COPD BMI underweight BMI super þ morbidly obese
1,323 (7.58) 32.5 ⫾ 12.9 3.3 ⫾ 1.10
2,791 (16.0) 31.8 ⫾ 12.8 3.2 ⫾ 1.05
0.085 0.037
13,345 (76.4) 31.3 ⫾ 12.3 3.0 ⫾ 1.02
o0.001 0.018
17,459 (100.0) 31.5 ⫾ 12.4 3.2 ⫾ 1.04
632 (47.8) 464 (35.1) 40 (3.0) 66 (5.0) 7 (0.5) 6 (0.5)
1,372 (49.2) 1,048 (37.5) 48 (1.7) 98 (3.5) 9 (0.3) 22 (0.8)
0.406 0.124 0.007 0.024 0.320 0.223
5,897 (44.2) 5,581 (41.8) 402 (3.0) 345 (2.6) 48 (0.4) 67 (0.5)
0.012 o0.001 0.982 o0.001 0.336 0.811
7,901 (45.3) 7,093 (40.6) 490 (2.8) 509 (2.9) 64 (0.4) 95 (0.5)
118 (8.9) 9 (0.7) 10 (0.8) 45 (3.4) 39 (2.9) 95 (7.2) 230 (17.4) 54.7 ⫾ 10.6 1,088 (82.2) 532 (40.2) 923 (69.8) 171 (12.9) 260 (19.7) 380 (28.7) 417 (31.5) 39 (2.9) 38 (2.9) 69 (5.2)
146 (5.2) 14 (0.5) 5 (0.2) 34 (1.2) 28 (1.0) 62 (2.2) 373 (13.4) 56.5 ⫾ 9.5 2,179 (78.1) 867 (31.1) 2,061 (73.8) 257 (9.2) 364 (13.0) 765 (27.4)) 910 (32.6) 97 (3.5) 60 (2.1) 133 (4.8)
o0.001 0.473 0.004 o0.001 o0.001 o0.001 0.001 o0.001 0.002 o0.001 0.006 o0.001 o0.001 0.339 0.135 0.281 0.155 0.530
671 (5.0) 15 (0.1) 21 (0.2) 346 (2.6) 129 (1.0) 588 (4.4) 2,454 (18.4) 50.8 ⫾ 12.6 10,489 (78.6) 3,915 (29.3) 10,329 (77.4) 1,326 (9.94) 1,556 (11.7) 2,805 (21.0)) 3,721 (27.9) 309 (2.3) 458 (3.4) 591 (4.4)
o0.001 0.094 o0.001 0.082 o0.001 o0.001 0.368 o0.001 0.002 o0.001 o0.001 0.001 o0.001 o0.001 0.186 0.326 0.261 0.211
935 (5.4) 38 (0.2) 36 (0.2) 425 (2.4) 196 (1.1) 745 (4.3) 3,057 (17.5) 52 ⫾ 12.2 13,756 (78.8) 5,314 (30.4) 13,313 (76.3) 1,754 (10.0) 2,180 (12.5) 3,950 (22.6) 5,048 (28.9) 445 (2.5) 556 (3.2) 793 (4.5)
BMI, body mass index; BVAD, biventricular assist device; COPD, chronic obstructive pulmonary disease; ECMO, extracorporeal membrane oxygenation; eGFR, estimated glomerular filtration rate EVAD, electric ventricular assist device; IABP, intraaortic balloon pump; ICU, intensive care unit; MCS, mechanical circulatory system; PVAD, pulsatile ventricular assist device; RVAD, right ventricle assist device. a Variables are shown as mean ⫾ standard deviation or number (%). b
p-value compared with eGFR r 34 ml/min.
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Figure 2 Kaplan-Meier graft survival analysis after transplantation by estimated glomerular filtration rate group (r 34, 35–49, and 449 ml/min), with number at risk by year after transplantation.
In multivariable logistic regression analysis, eGFR r 34 ml/min and eGFR 35–49 ml/min are significant risk factors for death at 1 year (p o 0.001). Other significant risk factors include ischemic time, mechanical circulatory support at transplant, donor age, hospitalization at time of transplant, congenital heart disease, total bilirubin 42.0 mg/dl, and hypertension (Table 3).
Secondary outcomes In-hospital morbidity: HD, stroke, and infection Incidence of in-hospital infection, stroke, and HD requirement are shown in Figure 4. Infection, stroke, and required HD occurred more frequently in the eGFR r 34 ml/min group compared with the eGFR 35–49 ml/min and the eGFR 4 49 ml/min groups (p o 0.001).
Long-term complications of transplantation Event-free survival from long-term complications of transplantation of severe infection, severe rejection, transplant
Figure 3 Kaplan-Meier graft survival analysis of conditional 1-year mortality after transplantation by estimated glomerular filtration rate group (r34, 35–49, and 4 49 ml/min).
Multivariable Logistic of Characteristics on Survival
Characteristics
OR (95% CI)
p-value
Transplant year Ischemic time Donor age Recipient characteristics eGFR r 34 ml/min eGFR 35–49ml/min Status 1 ICU at transplant BMI super þ morbidly obese BMI underweight Steroids Hospitalized Total bilirubin 4 2.0 mg/dl Diabetes mellitus Hypertensive COPD Cause of heart failure Ischemic Valvular Sarcoidosis Congenital Amyloidosis Life support at transplant BVAD MCS PVAD IABP RVAD MCS implantable device MCS EVAD ECMO
0.98 (0.95–1.01) 1.12 (1.06–1.19) 1.01 (1.01–1.02)
0.255 o0.001 o0.001
2.97 1.55 1.01 1.06 0.86
(2.50–3.53) (1.33–1.81) (0.85–1.21) (0.89–1.26) (0.63–1.17)
o0.001 o0.001 0.886 0.547 0.323
1.10 0.83 1.21 1.86 1.11 1.21 1.14
(0.78–1.54) (0.68–1.02) (1.06–1.36) (1.59–2.16) (0.97–1.29) (1.07–1.37) (0.84–1.57)
0.595 0.074 0.003 o0.001 0.136 0.003 0.400
1.11 1.07 1.69 2.54 1.88
(0.98–1.26) (0.71–1.62) (0.61–4.66) (1.90–3.40) (0.81–4.39)
0.098 0.738 0.309 o0.001 0.142
1.26 1.54 0.85 7.48 1.28 4.23 5.16
(0.82–1.93) (1.17–2.02) (0.645–1.11) (2.68–20.8) (1.01–1.50) (2.74–6.51) (2.14–12.4)
0.299 0.002 0.234 o0.001 0.003 o0.001 o0.001
BMI, body mass index; BVAD, biventricular assist device; CI, confidence interval; COPD, chronic obstructive pulmonary disease; ECMO, extracorporeal membrane oxygenation; EVAD, electric ventricular assist device; IABP, intraaortic balloon pump; ICU, intensive care unit; MCS, mechanical circulatory system; OR, odds ratio; PVAD, pulsatile ventricular assist device; RVAD, right ventricular assist device.
coronary artery disease (TCAD), stroke, and kidney failure are shown in Figure 5. Patients with eGFR r 34 ml/min are significantly more likely to develop severe infection resulting in hospitalization (p o 0.001) after OHT compared with the groups with eGFR 35–49 ml/min and eGFR 449 ml/min. Median time to severe infection was 5.1 years in the eGFR r 34 ml/min group and 7.0 years in the remaining higher eGFR groups. There were no differences in severe rejection, TCAD, or strokes among the eGFR groups. As expected, patients with pre-transplant eGFR r 34 ml/min were more likely to die or require renal replacement therapy, defined by HD or kidney transplant, than patients with relatively better preserved pre-transplant renal function (p o 0.001). Median time to death was 7.5 years in the eGFR r 34 group, 9.9 years in the eGFR 35–49 group, and 10.3 years in the eGFR 4 49 ml/min group (Figure 6). HD or preemptive renal transplant were required in 223 patients in the eGFR r 34 strata (16.9%),
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Figure 4 Incidence of in-hospital stroke, dialysis, and infection. *p o 0.05 compared with estimated glomerular filtration rate (eGFR) r 34 ml/min.
in 200 patients in the eGFR 35–49 strata (7.2%), and in 551 patients in the eGFR 4 49 strata (4.1%; Figure 7). In patients who required HD or renal transplant, median time was shorter (2.6 years) in patients with eGFR r 34 than in patients with eGFR 35–49 (3.8 years) and eGFR 449 ml/min (3.9 years).
Discussion This analysis supports the observation that pre-transplant renal insufficiency is a strong negative predictor of post-transplant graft survival.8–15 Although there was a statistical difference in survival between the eGFR 4 49
Figure 5 Kaplan-Meier analysis of long-term complication-free survival after transplantation by estimated glomerular filtration rate group (r34, 35–49, and 449 ml/min) with number at risk by year after transplantation. (a) Severe infection-free survival, defined as infection requiring hospitalization. (b) Severe rejection-free survival, defined as rejection requiring hospitalization. (c) Transplant coronary artery disease free survival. (d) Stroke free survival.
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The Journal of Heart and Lung Transplantation, Vol ], No ], Month ]]]] infections, strokes, and require HD. Consistent with previous studies, patients in the eGFR r 34 ml/min group were more likely to develop end-stage renal disease requiring HD or renal transplant.9–12,17–19 In addition, long-term infection rates were also higher in the eGFR r 34 ml/min group, but there was no difference in the incidence of rejection requiring hospitalization among the groups. Although, beyond the scope of this study, this observation suggests that resultant changes in posttransplant immunosuppression regimens as a result of kidney function did not significantly affect rejection rates.
Level of Evidence Figure 6 Kaplan-Meier analysis of renal failure end point of death by estimated glomerular filtration rate group (r 34, 35–49, and 449 ml/min).
and eGFR 35–49 ml/min groups, the median graft survival for both groups exceeded 10 years, and therefore, transplant offers good long-term outcomes for these patients. However, survival is decreased for patients in the eGFR r 34 ml/min group at all times. There is also notable decreased survival in the peri-operative period, evidenced by the initial steep drop in the survival curve. These results corroborate the study by Cantarovich et al16 determining that early decline in renal function is a strong negative predictor of survival. Median survival in this group was approximately 8 years, indicating that these patients do significantly worse than patients in either of the increased eGFR strata. Such results suggest that these organs might be better allocated to candidates with less severe renal impairment, or—based on findings from our previous study—that at least a sub-set of patients with an eGFR r 34 ml/min are more appropriately treated with combined heart-kidney transplant.8 These findings support the most recent ISHLT guidelines that CKD disease (eGFR r 40 ml/min) should be considered as a relative contraindication to OHT.3 Further analysis demonstrates that OHT recipients with worse renal function are also more likely to have in-hospital
Figure 7 Kaplan-Meier analysis of renal failure end point of dialysis or kidney transplantation by estimated glomerular filtration rate group (r34, 35–49, and 449 ml/min).
Commonly, clinical guidelines published by expert panels are based on Level C Evidence, which only requires evidence from expert committee reports or opinions and/or clinical experience of respected authorities. Tricoci et al20 found that a growing proportion of recommendations underlying American College of Cardiology/American Heart Association clinical practice guidelines were supported only by expert opinion and not objective data. The high proportion of guidelines supported by expert opinion only reflects the expense and resource intensiveness of conducting well-designed studies as well as the impracticality and inappropriateness of validating all details of clinical practice through randomized controlled trials. Further, some questions are not amenable to randomized studies. Nevertheless, these observations highlight the need for the clinical research community to explore questions that may provide objective evidence to guide the development of clinical guidelines. Owing to the nature of this question, which assesses post-transplant graft survival based on pretransplant risk factors, development of Level A Evidence, through a randomized clinical trial is impractical. This analysis of 17,459 OHTs provides sufficient Level B Evidence to support the ISHLT recommendation that eGFR r 40 ml/min is a relative contraindication to OHT alone.
Limitations First, consistent with the ISHLT guidelines, this current study evaluated eGFR as a continuous variable to stratify recipients based on risk. Estimated GFR is calculated using the age, gender, and serum creatinine of the patient. Several formulas have been developed to estimate GFR, including the Cockroft and Gault21 and the MDRD.22 Previous studies comparing various measurements favor the use of the MDRD formula, particularly in patients with severe congestive heart failure.23–25 The improved performance of the MDRD equation in this setting is largely due to the statistical modeling of muscle mass with the surrogate markers of age, sex, and race.26 Nevertheless, although other investigators,23,27–31 have applied similar approaches to characterize severity of CKD, a complex multidimensional construct, such as severity of disease, may not be fully characterized by any single or group of measures. For example, determining reversibility of kidney disease was not
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possible from the available data. Notably, 40.1% of the patients with eGFR o 34 ml/min in this study were in the intensive care unit, and 17.4% were supported by implantable mechanical assist devices and 8.9% by balloon pumps, suggesting that a greater percentage of this group of patients may have had reversible kidney disease. Nonetheless, our analysis demonstrates that despite having a greater proportion of patients with reversible kidney disease, these patients still have a worse post-transplant graft survival and higher rates of CKD over the long-term. Second, preoperative proteinuria was not available in this data set. Third, all patient registries often suffer from variability in data entry. However, since the passage of the National Transplantation Act of 1984 data entry has been mandatory for all United States transplant centers. Fields contained within this database were generally well populated, with a 95% to 99% data entry rate for most variables. Findings from this study, using large cohorts of patients, are unlikely to be affected by missing data. Fourth, the UNOS reporting system provides guidelines for defining conditions, such as cardiovascular accident, peripheral vascular disease, and rejection, but definitions may vary by center. Finally, other outcome issues must be considered, including quality of life, functionality, and return to work, in arriving at clinical decisions.
Conclusions The eGFR is a strong predictor of post-transplant survival and should be considered when assessing patients for cardiac transplant. Lower pre-transplant eGFR is associated with worse post-transplant graft survival, greater in-hospital morbidity, and higher rates of some CKD and infection over the long-term. This analysis demonstrates that eGFR r 34 ml/min is a strong negative of post-transplant survival and therefore may provide evidence to support the ISHLT guideline that CKD (eGFR o 40 ml/min) be considered as a relative contraindication for OHT. These patients may be more appropriate for combined heart-kidney transplantation. Finally, given the large proportion of guidelines based on expert opinion, the clinical research community must more aggressively pursue analyses that are useful for developing objective clinical guidelines.
Disclosure statement None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose. The authors thank UNOS for supplying these data and Jennifer Wainwright, PhD, for her assistance with the analysis. This work was partly by Health Resources and Services Administration contract 231–00–0115. The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
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References 1. Heart disease and stroke statistics–2005 update. Dallas, TX: American Heart Association, 2005. 2. The U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients (OPTN/SRTR) 2006 Annual Report. 2006. http://www.srtr.org/annual_reports/archives/ 2006/2006_Annual_Report/. Accessed March 30, 2016. 3. Mehra MR, Kobashigawa J, Starling R, et al. Listing criteria for heart transplantation: International Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates– 2006. J Heart Lung Transplant 2006;25:1024-42. 4. Hanley JA, McNeil BJ. A method of comparing the areas under receiver operating characteristic curves derived from the same cases. Radiology 1983;148:839-43. 5. Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 1982;143:29-36. 6. Peirce JC, Cornell RG. Integrating stratum-specific likelihood ratios with the analysis of ROC curves. Med Decis Making 1993;13:141-51. 7. Chen JM, Levin HR, Michler RE, Prusmack CJ, Rose EA, Aaronson KD. Reevaluating the significance of pulmonary hypertension before cardiac transplantation: determination of optimal thresholds and quantification of the effect of reversibility on perioperative mortality. J Thorac Cardiovasc Surg 1997;114:627-34. 8. Russo MJ, Rana A, Chen JM, et al. Pretransplantation patient characteristics and survival following combined heart and kidney transplantation: an analysis of the United Network for Organ Sharing Database. Arch Surg 2009;144:241-6. 9. Trachiotis GD, Vega JD, Johnston TS, et al. Ten-year follow-up in patients with combined heart and kidney transplantation. J Thorac Cardiovasc Surg 2003;126:2065-71. 10. Vossler MR, Ni H, Toy W, Hershberger RE. Pre-operative renal function predicts development of chronic renal insufficiency after orthotopic heart transplantation. J Heart Lung Transplant 2002;21:874-81. 11. Jokinen JJ, Tikkanen J, Kukkonen S, et al. Natural course and risk factors for impaired renal function during the first year after heart transplantation. J Heart Lung Transplant 2010;29:633-40. 12. Villar E, Boissonnat P, Sebbag L, et al. Poor prognosis of heart transplant patients with end-stage renal failure. Nephrol Dial Transplant 2007;22:1383-9. 13. Kniepeiss D, Wagner D, Wirnsberger G, et al. Serum cystatin C is an easy to obtain biomarker for the onset of renal impairment in heart transplant recipients. J Thorac Cardiovasc Surg 2010;140:688-93. 14. Lindelöw B, Bergh CH, Herlitz H, Waagstein F. Predictors and evolution of renal function during 9 years following heart transplantation. J Am Soc Nephrol 2000;11:951-7. 15. Ostermann ME, Rogers CA, Saeed I, et al. Pre-existing renal failure doubles 30-day mortality after heart transplantation. J Heart Lung Transplant 2004;23:1231-7. 16. Cantarovich M, Hirsh A, Alam A, et al. The clinical impact of an early decline in kidney function in patients following heart transplantation. Am J Transplant 2009;9:348-54. 17. Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med 2003;349:931-40. 18. Alam A, Badovinac K, Ivis F, Trpeski L, Cantarovich M. The outcome of heart transplant recipients following the development of end-stage renal disease: analysis of the Canadian Organ Replacement Register (CORR). Am J Transplant 2007;7:461-5. 19. Arora S, Andreassen A, Simonsen S, et al. Prognostic importance of renal function 1 year after heart transplantation for all-cause and cardiac mortality and development of allograft vasculopathy. Transplantation 2007;84:149-54. 20. Tricoci P, Allen JM, Kramer JM, Califf RM, Smith SC Jr. Scientific evidence underlying the ACC/AHA clinical practice guidelines. JAMA 2009;301:831-41. 21. Hoek FJ, Kemperman FA, Krediet RT. A comparison between cystatin C, plasma creatinine and the Cockroft and Gault formula for the estimation of glomerular filtration rate. Nephrol Dial Transplant 2003;18:2024-31. 22. Peters AM, Bird NJ, Halsall I, Peters C, Michell AR. Evaluation of the Modification of Diet in Renal Disease equation (eGFR) against
8
23.
24.
25.
26.
The Journal of Heart and Lung Transplantation, Vol ], No ], Month ]]]] simultaneous, dual-marker multi-sample measurements of glomerular filtration rate. Ann Clin Biochem 2009;46:58-64. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461-70. Smilde TD, van Veldhuisen DJ, Navis G, Voors AA, Hillege HL. Drawbacks and prognostic value of formulas estimating renal function in patients with chronic heart failure and systolic dysfunction. Circulation 2006;114:1572-80. Poggio ED, Wang X, Weinstein DM, Issa N, et al. Assessing glomerular filtration rate by estimation equations in kidney transplant recipients. Am J Transplant 2006;6:100-8. Poggio ED, Rule AD. Can we do better than a single estimated GFR threshold when screening for chronic kidney disease? Kidney Int 2007;72:534-6.
27. Tangri N, Stevens LA, Griffith J, et al. A predictive model for progression of chronic kidney disease to kidney failure. JAMA 2011; 305:1553-9. 28. Marsik C, Endler G, Gulesserian T, Wagner OF, Sunder-Plassmann G. Classification of chronic kidney disease by estimated glomerular filtration rate. Eur J Clin Invest 2008;38:253-9. 29. Mentzer RM Jr1, Oz MC, Sladen RN, et al. Effects of perioperative nesiritide in patients with left ventricular dysfunction undergoing cardiac surgery: the NAPA Trial. J Am Coll Cardiol 2007;49:716-26. 30. Damman K, van der Harst P, Smilde TD, et al. Use of cystatin C levels in estimating renal function and prognosis in patients with chronic systolic heart failure. Heart 2012;98:319-24. 31. Tangri N, Alam A, Giannetti N, Deedwardes MB, Cantarovich MN. Predicting glomerular filtration rate in heart transplant recipients using serum creatinine-based equations with cimetidine. J Heart Lung Transplant 2008;27:905-9.
ORIGINAL CLINICAL SCIENCE
Evidence supports severe renal insufficiency as a relative contraindication to heart transplantation Kimberly N. Hong, MD, MHSA,a Aurelie Merlo, BA,b Dhaval Chauhan, MD,c,d Ryan R. Davies, MD,e Alexander Iribarne, MD,f Elizabeth Johnson, MA,g Val Jeevanandam, MD,g and Mark J. Russo, MD, MSc,d From the aDepartment of Cardiology, Mount Sinai School of Medicine, New York, New York; b Case Western Reserve Medical School, Cleveland, Ohio; cDepartment of Surgery, Rutgers–New Jersey Medical School, Newark, New Jersey; dCardiovascular Clinical Research Unit, Barnabas Heart Hospitals, Newark, New Jersey e Division of Pediatric Cardiothoracic Surgery, Nemours/Alfred I. DuPont Hospital for Children, Wilmington, Delaware; f Department of Cardiothoracic Surgery, Dartmouth Medical Center, Hanover, New Hampshire g Section of Cardiac and Thoracic Surgery, Department of Surgery, University of Chicago, Chicago, Illinois.
KEYWORDS: orthotopic heart transplant; outcomes; mortality; renal insufficiency; estimated glomerular filtration rate; chronic kidney disease
BACKGROUND: This study was conducted to determine whether survival after orthotopic heart transplant (OHT) is associated with pre-transplant estimated glomerular filtration rate (eGFR) and to define ranges of pre-OHT eGFR associated with differences in post-transplant survival. The 2006 International Society for Heart and Lung Transplantation revised listing criteria for OHT stated that chronic kidney disease, defined by an eGFR o40 ml/min is a relative contraindication for OHT alone. The committee noted that this recommendation was supported by consensus opinion of experts and not data derived from a randomized trial or non-randomized studies. METHODS: The United Network for Organ Sharing provided deidentified patient-level data. The study population included 17,459 OHT recipients aged Z18 years who received allografts between January 1, 2001, and December 31, 2009. Logistic regression was used to assess the effect of multiple variables on survival after OHT. Receiver operating characteristic curves and stratum-specific likelihood ratios were generated to compare 1-year survival at eGFR thresholds. The primary outcomes measure was actuarial post-transplant survival expressed in years. RESULTS: Regression analysis showed that a lower pre-transplant eGFR is associated with worse posttransplant survival. Threshold analysis demonstrated 3 distinct survival strata: eGFR r 34 ml/min, eGFR 35 to 49 ml/min, and eGFR 4 49 ml/min. Graft survival at all times is decreased for patients with eGFR r 34 ml/min. They are also more likely to have in-hospital and long-term complications. CONCLUSIONS: eGFR is a strong predictor of post-transplant survival and should be considered when assessing patients for OHT. This analysis supports current International Society for Heart and Lung Transplantation guidelines and suggests that end-stage heart failure patients with an eGFR r 34 ml/min is a relative contraindication for heart transplantation alone. J Heart Lung Transplant ]]]];]:]]]–]]] r 2016 International Society for Heart and Lung Transplantation. All rights reserved.
Reprint requests: Dhaval Chauhan, MD, Department of Surgery,185 South Orange Avenue, Medical Science Building, Suite G-538, Newark, NJ 07103. Telephone: þ1-631-627-9166. E-mail address: [email protected]
End-stage heart failure is a significant problem in the United States. Currently, more than 60,000 deaths per year are directly attributed to end-stage disease, and an additional 250,000 patients with advanced stages of heart failure die from related causes.1 Orthotopic heart transplantation
1053-2498/$ - see front matter r 2016 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2016.02.003
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(OHT) remains the gold standard in the treatment of endstage heart failure. Unfortunately, due to a critical scarcity of available organs for transplantation, in any given year, fewer than 2,500 potential beneficiaries undergo OHT.2 Therefore, achieving maximal benefit from this therapy is predicated on improved patient selection. To this end, revised listing criteria for OHT were published by the International Society for Heart and Lung Transplantation (ISHLT) in 2006.3 The current guidelines state that chronic kidney disease (CKD), defined by an estimated glomerular filtration rate (eGFR) o 40 ml/min, is a relative contraindication for OHT alone. CKD has a strong association with end-stage heart failure, and is therefore commonly seen in OHT candidates. However, this recommendation related to severity of kidney disease and a candidate’s appropriateness for transplantation was supported only by consensus opinion (Level C Evidence) and not by objective data (Level A or B Evidence). A better body of evidence is clearly needed to refine future guidelines. We therefore, we chose to analyze the United Network for Organ Sharing (UNOS) database in an attempt to objectively define risks facing OHT recipients with various degrees of kidney disease. The purposes of this study were to (1) define ranges of eGFR before OHT associated with differences in post-transplant survival and (2) to describe post-transplant outcomes within eGFR strata.
Methods Data collection Use of these data is consistent with the regulations of the University of Chicago’s Institutional Review Board. UNOS provided deidentified patient-level data from the Thoracic Registry (data source 01052011–6). These data include all OHT recipients and donors in the United States and reported to the Organ Procurement and Transplantation Network between January 1, 2001, and December 31, 2009. Data entry by all United States transplant centers is mandated by the 1984 National Transplantation Act. The eGFR was calculated from pre-OHT serum creatinine using the Modification of Diet in Renal Disease (MDRD) Study Equation. Chronic dialysis patients were assigned an eGFR of 10 ml/min.
complications. Measures of transplant hospitalization morbidity included incidence of stroke, infection, and need for hemodialysis (HD) during the transplant hospitalization. Long-term complications were assessed by time-to-event analysis where the events of interest include transplant coronary artery disease (TCAD), chronic HD, severe infection, and severe rejection. HD-dependent recipients at transplant were dropped from the chronic HD–free survival analysis.
Data analysis Continuous variables are reported as means ⫾ standard deviation and were compared by using the Student’s t-test. Categoric variables were compared with the chi-square test. The conventional p-value value of 0.05 was used to determine statistical significance. All reported p-values are 2 sided.
Survival and other time-to-event analysis Kaplan-Meier analysis was used to calculate actuarial eventfree survival. For survival analysis, the outcome of interest was death (4,771 [27.0%]) or re-transplantation (198 [1.1%]). Other patients, including those lost to follow-up (526 [3.0%]) or alive at last follow-up (11,964 [69.0%]), were censored on the day of last known follow-up. To assess the simultaneous effect of multiple variables on the graft survival after OHT, multivariable logistic regression analysis (backward, p o 0.15) was used to determine the relationship between groups and 1-year graft survival. Long-term complications, excluding renal failure, were reported as event-free survival, where the outcome of interest was the specified complication. A composite end point that included death, HD, or renal transplantation was used to evaluate time to CKD stage 5 requiring HD.
Threshold analysis Receiver operating characteristic (ROC) curves and stratumspecific likelihood ratios (SSLR) were used in the threshold analysis to define eGFR strata. Receiver-operating characteristic curves were generated (Figure 1) by plotting sensitivity on the ordinate and 1–specificity on the abscissa with eGFR as a
Study population The study population included 17,459 first-time OHT patients aged 18 years and older between January 1, 2001, and December 31, 2009. The analysis excluded 980 patients because of lack of data (n ¼ 484) or because they were multiorgan transplant recipients (n ¼ 496). Patients were monitored from the date of transplantation to January 3, 2011, which was the last day of follow-up provided by UNOS.
Outcome measures The primary outcomes measure was actuarial post-transplant graft survival. Other outcomes of interest included primary graft failure at 1 year, transplant hospitalization morbidity, and long-term
Figure 1 Receiver operating characteristic (ROC) curve shows the estimated glomerular filtration rate as a predictor of 1-year mortality.
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continuous variable and mortality at 1 year as a binary outcome.4,5 SSLRs and 95% confidence intervals were generated using data cutpoints at regular intervals, as previously described.6,7 Cutpoints, or threshold values, for eGFR were determined by combining adjacent GFR strata with other statistically indistinct strata based on the presence of SSLRs with overlapping 95% confidence intervals. Cutpoints occurred when 2 statistically distinct strata could be formed. This process was repeated until no additional cutpoints were found.
3 Table 2
Estimated Glomerular Filtration Rate Strata
Strata
No.
SSLR (95% CI)
eGFR r 34 ml/min eGFR 35–49 ml/min eGFR 4 49 ml/min
1323 2791 13,345
2.53 (2.26–2.84) 1.22 (1.11–1.34) 0.83 (0.80–0.85)
CI, confidence interval; eGFR, estimated glomerular filtration rate; SSLR, stratum-specific likelihood ratio.
Primary outcomes
Results Study population The study population included 17,459 first-time OHT recipients. Mean follow-up was 4.15 ⫾ 2.96 years (range, 0–11.09 years). Clinical characteristics of the study population are included in Table 1. Threshold analysis generated three separate eGFR strata (ml/min): eGFR r 34 (1,323 [7.6%]), eGFR 35 to 49 (2,791 [16.0%]), and eGFR 4 49 (13,345 [76.4%]; Table 2). Table 1
Post-transplant graft survival in the eGFR r 34 ml/min group is significantly worse than in the eGFR 35–49 ml/ min/ or eGFR 4 49 ml/min groups (p o 0.001), with median survival in the 3 groups at 8.2 years, 10.0 years, and 10.3 years, respectively. At 3 months, graft survival was 82.1%, 90.7%, and 94.0% in the eGFR r 34 ml/min, eGFR 35–49 ml/min, and eGFR 449 ml/min groups, respectively. This reduced graft survival persists at all post-transplant time points (Figure 2). Conditional 1-year survival is shown in Figure 3.
Patient Characteristics for all Heart Transplant Recipients Aged 18 Years and Older (2001–2009)
Variablea
eGFR r 34 ml/min eGFR 35–49 ml/min p-valueb eGFR 4 49 ml/min p-valueb Total
Heart transplant recipients Donor age, years Donor organ ischemic time, hours Cause of heart failure Ischemic Dilated Congenital Valvular Sarcoidosis Amyloidosis Life support at transplant IABP ECMO RVAD BVAD MCS EVAD MCS PVAD MCS implantable device Age, years Status 1 at transplant ICU at transplant Male sex Steroids Total bilirubin 4 2.0 mg/dl Diabetes mellitus Hypertensive COPD BMI underweight BMI super þ morbidly obese
1,323 (7.58) 32.5 ⫾ 12.9 3.3 ⫾ 1.10
2,791 (16.0) 31.8 ⫾ 12.8 3.2 ⫾ 1.05
0.085 0.037
13,345 (76.4) 31.3 ⫾ 12.3 3.0 ⫾ 1.02
o0.001 0.018
17,459 (100.0) 31.5 ⫾ 12.4 3.2 ⫾ 1.04
632 (47.8) 464 (35.1) 40 (3.0) 66 (5.0) 7 (0.5) 6 (0.5)
1,372 (49.2) 1,048 (37.5) 48 (1.7) 98 (3.5) 9 (0.3) 22 (0.8)
0.406 0.124 0.007 0.024 0.320 0.223
5,897 (44.2) 5,581 (41.8) 402 (3.0) 345 (2.6) 48 (0.4) 67 (0.5)
0.012 o0.001 0.982 o0.001 0.336 0.811
7,901 (45.3) 7,093 (40.6) 490 (2.8) 509 (2.9) 64 (0.4) 95 (0.5)
118 (8.9) 9 (0.7) 10 (0.8) 45 (3.4) 39 (2.9) 95 (7.2) 230 (17.4) 54.7 ⫾ 10.6 1,088 (82.2) 532 (40.2) 923 (69.8) 171 (12.9) 260 (19.7) 380 (28.7) 417 (31.5) 39 (2.9) 38 (2.9) 69 (5.2)
146 (5.2) 14 (0.5) 5 (0.2) 34 (1.2) 28 (1.0) 62 (2.2) 373 (13.4) 56.5 ⫾ 9.5 2,179 (78.1) 867 (31.1) 2,061 (73.8) 257 (9.2) 364 (13.0) 765 (27.4)) 910 (32.6) 97 (3.5) 60 (2.1) 133 (4.8)
o0.001 0.473 0.004 o0.001 o0.001 o0.001 0.001 o0.001 0.002 o0.001 0.006 o0.001 o0.001 0.339 0.135 0.281 0.155 0.530
671 (5.0) 15 (0.1) 21 (0.2) 346 (2.6) 129 (1.0) 588 (4.4) 2,454 (18.4) 50.8 ⫾ 12.6 10,489 (78.6) 3,915 (29.3) 10,329 (77.4) 1,326 (9.94) 1,556 (11.7) 2,805 (21.0)) 3,721 (27.9) 309 (2.3) 458 (3.4) 591 (4.4)
o0.001 0.094 o0.001 0.082 o0.001 o0.001 0.368 o0.001 0.002 o0.001 o0.001 0.001 o0.001 o0.001 0.186 0.326 0.261 0.211
935 (5.4) 38 (0.2) 36 (0.2) 425 (2.4) 196 (1.1) 745 (4.3) 3,057 (17.5) 52 ⫾ 12.2 13,756 (78.8) 5,314 (30.4) 13,313 (76.3) 1,754 (10.0) 2,180 (12.5) 3,950 (22.6) 5,048 (28.9) 445 (2.5) 556 (3.2) 793 (4.5)
BMI, body mass index; BVAD, biventricular assist device; COPD, chronic obstructive pulmonary disease; ECMO, extracorporeal membrane oxygenation; eGFR, estimated glomerular filtration rate EVAD, electric ventricular assist device; IABP, intraaortic balloon pump; ICU, intensive care unit; MCS, mechanical circulatory system; PVAD, pulsatile ventricular assist device; RVAD, right ventricle assist device. a Variables are shown as mean ⫾ standard deviation or number (%). b
p-value compared with eGFR r 34 ml/min.
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Figure 2 Kaplan-Meier graft survival analysis after transplantation by estimated glomerular filtration rate group (r 34, 35–49, and 449 ml/min), with number at risk by year after transplantation.
In multivariable logistic regression analysis, eGFR r 34 ml/min and eGFR 35–49 ml/min are significant risk factors for death at 1 year (p o 0.001). Other significant risk factors include ischemic time, mechanical circulatory support at transplant, donor age, hospitalization at time of transplant, congenital heart disease, total bilirubin 42.0 mg/dl, and hypertension (Table 3).
Secondary outcomes In-hospital morbidity: HD, stroke, and infection Incidence of in-hospital infection, stroke, and HD requirement are shown in Figure 4. Infection, stroke, and required HD occurred more frequently in the eGFR r 34 ml/min group compared with the eGFR 35–49 ml/min and the eGFR 4 49 ml/min groups (p o 0.001).
Long-term complications of transplantation Event-free survival from long-term complications of transplantation of severe infection, severe rejection, transplant
Figure 3 Kaplan-Meier graft survival analysis of conditional 1-year mortality after transplantation by estimated glomerular filtration rate group (r34, 35–49, and 4 49 ml/min).
Multivariable Logistic of Characteristics on Survival
Characteristics
OR (95% CI)
p-value
Transplant year Ischemic time Donor age Recipient characteristics eGFR r 34 ml/min eGFR 35–49ml/min Status 1 ICU at transplant BMI super þ morbidly obese BMI underweight Steroids Hospitalized Total bilirubin 4 2.0 mg/dl Diabetes mellitus Hypertensive COPD Cause of heart failure Ischemic Valvular Sarcoidosis Congenital Amyloidosis Life support at transplant BVAD MCS PVAD IABP RVAD MCS implantable device MCS EVAD ECMO
0.98 (0.95–1.01) 1.12 (1.06–1.19) 1.01 (1.01–1.02)
0.255 o0.001 o0.001
2.97 1.55 1.01 1.06 0.86
(2.50–3.53) (1.33–1.81) (0.85–1.21) (0.89–1.26) (0.63–1.17)
o0.001 o0.001 0.886 0.547 0.323
1.10 0.83 1.21 1.86 1.11 1.21 1.14
(0.78–1.54) (0.68–1.02) (1.06–1.36) (1.59–2.16) (0.97–1.29) (1.07–1.37) (0.84–1.57)
0.595 0.074 0.003 o0.001 0.136 0.003 0.400
1.11 1.07 1.69 2.54 1.88
(0.98–1.26) (0.71–1.62) (0.61–4.66) (1.90–3.40) (0.81–4.39)
0.098 0.738 0.309 o0.001 0.142
1.26 1.54 0.85 7.48 1.28 4.23 5.16
(0.82–1.93) (1.17–2.02) (0.645–1.11) (2.68–20.8) (1.01–1.50) (2.74–6.51) (2.14–12.4)
0.299 0.002 0.234 o0.001 0.003 o0.001 o0.001
BMI, body mass index; BVAD, biventricular assist device; CI, confidence interval; COPD, chronic obstructive pulmonary disease; ECMO, extracorporeal membrane oxygenation; EVAD, electric ventricular assist device; IABP, intraaortic balloon pump; ICU, intensive care unit; MCS, mechanical circulatory system; OR, odds ratio; PVAD, pulsatile ventricular assist device; RVAD, right ventricular assist device.
coronary artery disease (TCAD), stroke, and kidney failure are shown in Figure 5. Patients with eGFR r 34 ml/min are significantly more likely to develop severe infection resulting in hospitalization (p o 0.001) after OHT compared with the groups with eGFR 35–49 ml/min and eGFR 449 ml/min. Median time to severe infection was 5.1 years in the eGFR r 34 ml/min group and 7.0 years in the remaining higher eGFR groups. There were no differences in severe rejection, TCAD, or strokes among the eGFR groups. As expected, patients with pre-transplant eGFR r 34 ml/min were more likely to die or require renal replacement therapy, defined by HD or kidney transplant, than patients with relatively better preserved pre-transplant renal function (p o 0.001). Median time to death was 7.5 years in the eGFR r 34 group, 9.9 years in the eGFR 35–49 group, and 10.3 years in the eGFR 4 49 ml/min group (Figure 6). HD or preemptive renal transplant were required in 223 patients in the eGFR r 34 strata (16.9%),
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Figure 4 Incidence of in-hospital stroke, dialysis, and infection. *p o 0.05 compared with estimated glomerular filtration rate (eGFR) r 34 ml/min.
in 200 patients in the eGFR 35–49 strata (7.2%), and in 551 patients in the eGFR 4 49 strata (4.1%; Figure 7). In patients who required HD or renal transplant, median time was shorter (2.6 years) in patients with eGFR r 34 than in patients with eGFR 35–49 (3.8 years) and eGFR 449 ml/min (3.9 years).
Discussion This analysis supports the observation that pre-transplant renal insufficiency is a strong negative predictor of post-transplant graft survival.8–15 Although there was a statistical difference in survival between the eGFR 4 49
Figure 5 Kaplan-Meier analysis of long-term complication-free survival after transplantation by estimated glomerular filtration rate group (r34, 35–49, and 449 ml/min) with number at risk by year after transplantation. (a) Severe infection-free survival, defined as infection requiring hospitalization. (b) Severe rejection-free survival, defined as rejection requiring hospitalization. (c) Transplant coronary artery disease free survival. (d) Stroke free survival.
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The Journal of Heart and Lung Transplantation, Vol ], No ], Month ]]]] infections, strokes, and require HD. Consistent with previous studies, patients in the eGFR r 34 ml/min group were more likely to develop end-stage renal disease requiring HD or renal transplant.9–12,17–19 In addition, long-term infection rates were also higher in the eGFR r 34 ml/min group, but there was no difference in the incidence of rejection requiring hospitalization among the groups. Although, beyond the scope of this study, this observation suggests that resultant changes in posttransplant immunosuppression regimens as a result of kidney function did not significantly affect rejection rates.
Level of Evidence Figure 6 Kaplan-Meier analysis of renal failure end point of death by estimated glomerular filtration rate group (r 34, 35–49, and 449 ml/min).
and eGFR 35–49 ml/min groups, the median graft survival for both groups exceeded 10 years, and therefore, transplant offers good long-term outcomes for these patients. However, survival is decreased for patients in the eGFR r 34 ml/min group at all times. There is also notable decreased survival in the peri-operative period, evidenced by the initial steep drop in the survival curve. These results corroborate the study by Cantarovich et al16 determining that early decline in renal function is a strong negative predictor of survival. Median survival in this group was approximately 8 years, indicating that these patients do significantly worse than patients in either of the increased eGFR strata. Such results suggest that these organs might be better allocated to candidates with less severe renal impairment, or—based on findings from our previous study—that at least a sub-set of patients with an eGFR r 34 ml/min are more appropriately treated with combined heart-kidney transplant.8 These findings support the most recent ISHLT guidelines that CKD disease (eGFR r 40 ml/min) should be considered as a relative contraindication to OHT.3 Further analysis demonstrates that OHT recipients with worse renal function are also more likely to have in-hospital
Figure 7 Kaplan-Meier analysis of renal failure end point of dialysis or kidney transplantation by estimated glomerular filtration rate group (r34, 35–49, and 449 ml/min).
Commonly, clinical guidelines published by expert panels are based on Level C Evidence, which only requires evidence from expert committee reports or opinions and/or clinical experience of respected authorities. Tricoci et al20 found that a growing proportion of recommendations underlying American College of Cardiology/American Heart Association clinical practice guidelines were supported only by expert opinion and not objective data. The high proportion of guidelines supported by expert opinion only reflects the expense and resource intensiveness of conducting well-designed studies as well as the impracticality and inappropriateness of validating all details of clinical practice through randomized controlled trials. Further, some questions are not amenable to randomized studies. Nevertheless, these observations highlight the need for the clinical research community to explore questions that may provide objective evidence to guide the development of clinical guidelines. Owing to the nature of this question, which assesses post-transplant graft survival based on pretransplant risk factors, development of Level A Evidence, through a randomized clinical trial is impractical. This analysis of 17,459 OHTs provides sufficient Level B Evidence to support the ISHLT recommendation that eGFR r 40 ml/min is a relative contraindication to OHT alone.
Limitations First, consistent with the ISHLT guidelines, this current study evaluated eGFR as a continuous variable to stratify recipients based on risk. Estimated GFR is calculated using the age, gender, and serum creatinine of the patient. Several formulas have been developed to estimate GFR, including the Cockroft and Gault21 and the MDRD.22 Previous studies comparing various measurements favor the use of the MDRD formula, particularly in patients with severe congestive heart failure.23–25 The improved performance of the MDRD equation in this setting is largely due to the statistical modeling of muscle mass with the surrogate markers of age, sex, and race.26 Nevertheless, although other investigators,23,27–31 have applied similar approaches to characterize severity of CKD, a complex multidimensional construct, such as severity of disease, may not be fully characterized by any single or group of measures. For example, determining reversibility of kidney disease was not
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possible from the available data. Notably, 40.1% of the patients with eGFR o 34 ml/min in this study were in the intensive care unit, and 17.4% were supported by implantable mechanical assist devices and 8.9% by balloon pumps, suggesting that a greater percentage of this group of patients may have had reversible kidney disease. Nonetheless, our analysis demonstrates that despite having a greater proportion of patients with reversible kidney disease, these patients still have a worse post-transplant graft survival and higher rates of CKD over the long-term. Second, preoperative proteinuria was not available in this data set. Third, all patient registries often suffer from variability in data entry. However, since the passage of the National Transplantation Act of 1984 data entry has been mandatory for all United States transplant centers. Fields contained within this database were generally well populated, with a 95% to 99% data entry rate for most variables. Findings from this study, using large cohorts of patients, are unlikely to be affected by missing data. Fourth, the UNOS reporting system provides guidelines for defining conditions, such as cardiovascular accident, peripheral vascular disease, and rejection, but definitions may vary by center. Finally, other outcome issues must be considered, including quality of life, functionality, and return to work, in arriving at clinical decisions.
Conclusions The eGFR is a strong predictor of post-transplant survival and should be considered when assessing patients for cardiac transplant. Lower pre-transplant eGFR is associated with worse post-transplant graft survival, greater in-hospital morbidity, and higher rates of some CKD and infection over the long-term. This analysis demonstrates that eGFR r 34 ml/min is a strong negative of post-transplant survival and therefore may provide evidence to support the ISHLT guideline that CKD (eGFR o 40 ml/min) be considered as a relative contraindication for OHT. These patients may be more appropriate for combined heart-kidney transplantation. Finally, given the large proportion of guidelines based on expert opinion, the clinical research community must more aggressively pursue analyses that are useful for developing objective clinical guidelines.
Disclosure statement None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose. The authors thank UNOS for supplying these data and Jennifer Wainwright, PhD, for her assistance with the analysis. This work was partly by Health Resources and Services Administration contract 231–00–0115. The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
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References 1. Heart disease and stroke statistics–2005 update. Dallas, TX: American Heart Association, 2005. 2. The U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients (OPTN/SRTR) 2006 Annual Report. 2006. http://www.srtr.org/annual_reports/archives/ 2006/2006_Annual_Report/. Accessed March 30, 2016. 3. Mehra MR, Kobashigawa J, Starling R, et al. Listing criteria for heart transplantation: International Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates– 2006. J Heart Lung Transplant 2006;25:1024-42. 4. Hanley JA, McNeil BJ. A method of comparing the areas under receiver operating characteristic curves derived from the same cases. Radiology 1983;148:839-43. 5. Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 1982;143:29-36. 6. Peirce JC, Cornell RG. Integrating stratum-specific likelihood ratios with the analysis of ROC curves. Med Decis Making 1993;13:141-51. 7. Chen JM, Levin HR, Michler RE, Prusmack CJ, Rose EA, Aaronson KD. Reevaluating the significance of pulmonary hypertension before cardiac transplantation: determination of optimal thresholds and quantification of the effect of reversibility on perioperative mortality. J Thorac Cardiovasc Surg 1997;114:627-34. 8. Russo MJ, Rana A, Chen JM, et al. Pretransplantation patient characteristics and survival following combined heart and kidney transplantation: an analysis of the United Network for Organ Sharing Database. Arch Surg 2009;144:241-6. 9. Trachiotis GD, Vega JD, Johnston TS, et al. Ten-year follow-up in patients with combined heart and kidney transplantation. J Thorac Cardiovasc Surg 2003;126:2065-71. 10. Vossler MR, Ni H, Toy W, Hershberger RE. Pre-operative renal function predicts development of chronic renal insufficiency after orthotopic heart transplantation. J Heart Lung Transplant 2002;21:874-81. 11. Jokinen JJ, Tikkanen J, Kukkonen S, et al. Natural course and risk factors for impaired renal function during the first year after heart transplantation. J Heart Lung Transplant 2010;29:633-40. 12. Villar E, Boissonnat P, Sebbag L, et al. Poor prognosis of heart transplant patients with end-stage renal failure. Nephrol Dial Transplant 2007;22:1383-9. 13. Kniepeiss D, Wagner D, Wirnsberger G, et al. Serum cystatin C is an easy to obtain biomarker for the onset of renal impairment in heart transplant recipients. J Thorac Cardiovasc Surg 2010;140:688-93. 14. Lindelöw B, Bergh CH, Herlitz H, Waagstein F. Predictors and evolution of renal function during 9 years following heart transplantation. J Am Soc Nephrol 2000;11:951-7. 15. Ostermann ME, Rogers CA, Saeed I, et al. Pre-existing renal failure doubles 30-day mortality after heart transplantation. J Heart Lung Transplant 2004;23:1231-7. 16. Cantarovich M, Hirsh A, Alam A, et al. The clinical impact of an early decline in kidney function in patients following heart transplantation. Am J Transplant 2009;9:348-54. 17. Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med 2003;349:931-40. 18. Alam A, Badovinac K, Ivis F, Trpeski L, Cantarovich M. The outcome of heart transplant recipients following the development of end-stage renal disease: analysis of the Canadian Organ Replacement Register (CORR). Am J Transplant 2007;7:461-5. 19. Arora S, Andreassen A, Simonsen S, et al. Prognostic importance of renal function 1 year after heart transplantation for all-cause and cardiac mortality and development of allograft vasculopathy. Transplantation 2007;84:149-54. 20. Tricoci P, Allen JM, Kramer JM, Califf RM, Smith SC Jr. Scientific evidence underlying the ACC/AHA clinical practice guidelines. JAMA 2009;301:831-41. 21. Hoek FJ, Kemperman FA, Krediet RT. A comparison between cystatin C, plasma creatinine and the Cockroft and Gault formula for the estimation of glomerular filtration rate. Nephrol Dial Transplant 2003;18:2024-31. 22. Peters AM, Bird NJ, Halsall I, Peters C, Michell AR. Evaluation of the Modification of Diet in Renal Disease equation (eGFR) against
8
23.
24.
25.
26.
The Journal of Heart and Lung Transplantation, Vol ], No ], Month ]]]] simultaneous, dual-marker multi-sample measurements of glomerular filtration rate. Ann Clin Biochem 2009;46:58-64. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461-70. Smilde TD, van Veldhuisen DJ, Navis G, Voors AA, Hillege HL. Drawbacks and prognostic value of formulas estimating renal function in patients with chronic heart failure and systolic dysfunction. Circulation 2006;114:1572-80. Poggio ED, Wang X, Weinstein DM, Issa N, et al. Assessing glomerular filtration rate by estimation equations in kidney transplant recipients. Am J Transplant 2006;6:100-8. Poggio ED, Rule AD. Can we do better than a single estimated GFR threshold when screening for chronic kidney disease? Kidney Int 2007;72:534-6.
27. Tangri N, Stevens LA, Griffith J, et al. A predictive model for progression of chronic kidney disease to kidney failure. JAMA 2011; 305:1553-9. 28. Marsik C, Endler G, Gulesserian T, Wagner OF, Sunder-Plassmann G. Classification of chronic kidney disease by estimated glomerular filtration rate. Eur J Clin Invest 2008;38:253-9. 29. Mentzer RM Jr1, Oz MC, Sladen RN, et al. Effects of perioperative nesiritide in patients with left ventricular dysfunction undergoing cardiac surgery: the NAPA Trial. J Am Coll Cardiol 2007;49:716-26. 30. Damman K, van der Harst P, Smilde TD, et al. Use of cystatin C levels in estimating renal function and prognosis in patients with chronic systolic heart failure. Heart 2012;98:319-24. 31. Tangri N, Alam A, Giannetti N, Deedwardes MB, Cantarovich MN. Predicting glomerular filtration rate in heart transplant recipients using serum creatinine-based equations with cimetidine. J Heart Lung Transplant 2008;27:905-9.