# Renal Impairment an Impediment to Heart Transplantation?

Cédric Rafat, Alexandre Hertig, Eric Rondeau

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## To cite this version:

Cédric Rafat, Alexandre Hertig, Eric Rondeau. Renal Impairment an Impediment to Heart Transplantation?. Iranian Journal of Kidney Diseases, 2015, 9 (2), pp.77-83. hal-01270977

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# Renal Impairment an Impediment to Heart Transplantation?

Cédric Rafat,¹ Alexandre Hertig,¹,² Eric Rondeau¹,²

¹APHP, Hôpital Tenon,
Department of Renal
Emergencies and Kidney
Transplantation, Paris, France

²Pierre and Marie Curie
University, Sorbonne
Universities, Paris, France

**Keywords.** heart
transplantation, chronic kidney
disease, preoperative care

Chronic kidney disease and chronic heart failure are now recognized as closely intertwined entities. The noxious interactions between the heart and kidney systems as part of the so-called *cardiorenal syndrome* is a matter of great concern for heart transplant candidates. Not only is chronic kidney disease a commonly associated comorbidity, but its detrimental effect on the outcome of heart transplantation is now well established. In the more advanced stages of kidney disease, it may even deter physicians from carrying out heart transplantation in potential candidates. This review offers insights on epidemiological issues regarding chronic kidney disease among patients awaiting heart transplantation as well as its impact on the outcomes related with heart transplantations. Finally, emerging therapeutic opportunities which may benefit heart transplant candidates with the most severe renal impairment will be reviewed with a special emphasis on combined heart-kidney transplantation.

IJKD 2015;9:77-83
www.ijkd.org

## INTRODUCTION

Chronic kidney disease (CKD), especially when severe, is widely held as a contraindication to heart transplantation by many medical institutions. Given the widespread prevalence of CKD among heart transplant candidates, a nephrological assessment and management in potential heart transplant recipients is a key issue as renal impairment may potentially jeopardize the access of these patients to a life-saving procedure. Chronic heart and kidney diseases are intimately interconnected. First, both conditions share a great number of etiological factors. Second, a steady stream of studies has highlighted the negative heart-kidney interaction in such a way that any acute or chronic dysfunction of the former may affect the latter, and reciprocally, as part of the *cardiorenal syndromes*.

## EPIDEMIOLOGY

### Prevalence of Chronic Kidney Disease Among
Candidates for Heart Transplantation

In the 2009 annual report of the United States
Renal Data System, a near two-third of the patients

with CKD also presented with cardiovascular
disease. This stands in stark contrast with the
population of patients unaffected by kidney
dysfunction among whom a cardiovascular
condition was present only in a mere 5.8% of the
cases. Furthermore, heart failure emerged as the
cardiovascular condition the most closely associated
with CKD.¹ Reciprocally, a recent meta-analysis
designed to determine the prevalence of CKD
among patients suffering from heart failure found
that 29% among the latter fulfilled the criteria for
moderate or severe CKD (estimated glomerular
filtration rate [GFR], < 60 mL/min).² Of note, the
prevalence of CKD remains high regardless of the
nature and severity of heart failure, including in
patients who exhibit a normal ejection fraction.³⁻⁵
The ominous significance of CKD in this setting
is now well recognized and has been shown to
be associated with an increased mortality rate.⁶
In France, data stemming from the Agence de la
biomédecine indicate that one-third of the patients
awaiting heart transplantation have concurrent
CKD. Elsewhere, figures ranging from 15% to 25%
have been reported.⁷,⁸
## The Impact of Post-Heart-Transplantation Chronic Kidney Disease

Heart transplant patients should be regarded as particularly vulnerable to the occurrence of CKD and this includes end-stage renal disease (ESRD). In this respect, cohort studies have established that between 2% to 18% of heart transplant patients develop ESRD requiring permanent hemodialysis. Reported time lapses between heart transplantation and the onset of ESRD range between 72 and 120 months (Table).<sup>7,9-28</sup> Patients usually display maximum loss of kidney function during the first year following transplantation. Ten years after heart transplantation, less than 10% of the patients exhibit a normal kidney function (estimated GFR, > 90 mL/min), doubling of serum creatinine is observed in more than half of them and an approximate 40% demonstrate severely altered kidney function (estimated GFR, < 20 mL/min).<sup>12,14,18,22</sup> The occurrence of ESRD in heart transplant patients also represents a major turning point in the course of heart transplantation as it is associated with a significantly enhanced risk of mortality. Furthermore, the impact of post-heart-transplantation CKD stretches beyond its effect on patients' survival rate as it has been shown to significantly alter heart transplant recipients' cardiopulmonary performance during exercise as well as their quality of life.<sup>29</sup>

## Preoperative Chronic Kidney Disease and Its Associated Risks

In the setting of cardiac surgery, the unfavorable impact of preoperative kidney failure on the outcome of surgical patients is a well-known fact. More specifically, CKD has been linked to an increased intra- and extra-hospital mortality and predicted the occurrence of postoperative acute kidney injury (AKI).<sup>30-35</sup> Moreover, CKD also impedes cardiac rehabilitation following surgery. Similar findings have been established in heart transplant patients, preexistent CKD portends an ominous prognosis with a heightened risk of mortality.<sup>20,27</sup> In this regard, Ostermann and colleagues evidenced that the postoperative 30-day mortality doubled in the subgroup of patients whose glomerular filtration rate was lower than 50 mL/min.<sup>20</sup> Likewise, preoperative CKD is also an independent risk factor for postoperative AKI both a frequent and dreaded complication. In a

retrospective monocentric study based on 307 heart transplant recipients, AKI occurred in 40% of the patients in the early stages after surgery and extrarenal epuration (ERE) was required in 6% of the patients.<sup>21,24,36</sup> Even higher figures have been reported in other studies (Table). The more severe the AKI, the more likely patients are to die, yet another indication of the intimate connection between kidney failure and the adverse outcome of heart transplantation.<sup>36,37</sup> Furthermore, the occurrence of severe AKI (as defined as AKI requiring ERE) compromises the patient's long-term kidney function with an increased likelihood of CKD.<sup>21</sup> This phenomenon should be interpreted in a broader reappraisal of AKI in general. Long seen as benign event in the sense that full kidney function recovery of AKI was almost universally expected, AKI has now been proven to predispose to CKD.<sup>38,39</sup>

Finally, the kidney function threshold below which heart transplantation should not be performed remains elusive. Nevertheless, some studies have stated that a GFR below 30 mL/min or 40 mL/min may be a reasonable set point.<sup>40</sup> One word should also be said about the "waiting list phenomenon," which lends further confusion when addressing the issue of kidney function of heart transplant candidates. Given the previously mentioned negative heart-kidney interplay, on the one hand, and the significant delay between when patients are cleared for heart transplantation and the transplantation itself, on the other hand, kidney function may deteriorate in the meanwhile. Hence, patients may have a suitable kidney function at initial screening but may fail to achieve the minimum requirements on transplantation day. In fact, Ostermann and colleagues reported that more than half of the patients displayed significant worsening of their kidney function between enrolment for transplantation and surgery.<sup>20</sup>

## Chronic Kidney Disease Risk Factors After Heart Transplantation

A retrospective analysis encompassing more than 24 000 heart and combined heart-and-lung transplantations has shed light on risk factors associated with the occurrence of CKD, namely advanced age, arterial hypertension and diabetes (prior to transplantation), and hepatitis C virus infection.<sup>8,41</sup> Calcineurin inhibitors (tacrolimus and
Epidemiology and Impact of Preoperative Chronic Kidney Disease in the Heart Transplant Recipients*

<table><thead><tr><th rowspan="2">Author</th><th rowspan="2">Publication Year</th><th rowspan="2">Study Design</th><th rowspan="2">Median Posttransplant Follow-up, mo</th><th rowspan="2">Number of Patients</th><th colspan="3">ESRD as Outcome</th><th colspan="3">AKI as Outcome</th></tr><tr><th>%</th><th>Time to Onset, mo</th><th>Preoperative CKD as a Risk Factor</th><th>Other Risk Factors</th><th>%</th><th>Preoperative CKD Patients as a Risk Factor</th><th>Preoperative CKD Risk Factor for Mortality</th></tr></thead><tbody><tr><td>van Gelder et al<sup>11</sup></td><td>1998</td><td>CC</td><td>79</td><td>304</td><td>8</td><td>79</td><td>No</td><td>None</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Hornberger et al<sup>16</sup></td><td>1998</td><td>RS</td><td>...</td><td>2088</td><td>2</td><td>...</td><td>...</td><td>...</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Hamour et al<sup>12</sup></td><td>1999</td><td>RS</td><td>60</td><td>352</td><td>3</td><td>...</td><td>No</td><td>AKI, Female, DM2</td><td>23.6</td><td>...</td><td>...</td></tr><tr><td>Lindelőw et al<sup>14</sup></td><td>2000</td><td>RS</td><td>120</td><td>151</td><td>4</td><td>...</td><td>No</td><td>...</td><td>10.8</td><td>...</td><td>...</td></tr><tr><td>Satchithananda et al<sup>17</sup></td><td>2002</td><td>RS</td><td>63</td><td>697</td><td>5.8</td><td>87</td><td>No</td><td>None</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Vossler et al<sup>15</sup></td><td>2002</td><td>RS</td><td>50</td><td>160</td><td>3.8</td><td>...</td><td>Yes</td><td>Age, ICM</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Sénéchéal et al<sup>18</sup></td><td>2004</td><td>CC</td><td>160</td><td>1211</td><td>3</td><td>120</td><td>Yes</td><td>...</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Rubel et al<sup>19</sup></td><td>2004</td><td>RS</td><td>...</td><td>370</td><td>6</td><td>75.6</td><td>Yes</td><td>Cyclosporine, DM2</td><td>19</td><td>...</td><td>...</td></tr><tr><td>Ostermann et al<sup>20</sup></td><td>2004</td><td>RS</td><td>1</td><td>1180</td><td>...</td><td>...</td><td>...</td><td>...</td><td>13.4</td><td>...</td><td>Yes</td></tr><tr><td>Odim et al<sup>7</sup></td><td>2005</td><td>RS</td><td>...</td><td>622</td><td>...</td><td>...</td><td>...</td><td>Age, ICM</td><td>12.9</td><td>No</td><td>No</td></tr><tr><td>Boyle et al<sup>21</sup></td><td>2006</td><td>RS</td><td>...</td><td>756</td><td>...</td><td>...</td><td>...</td><td>...</td><td>5.8</td><td>Yes</td><td>...</td></tr><tr><td>Canales et al<sup>22</sup></td><td>2006</td><td>RS</td><td>79</td><td>219</td><td>7.3</td><td>...</td><td>No</td><td>Age, Cyclosporine</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Lubitz et al<sup>13</sup></td><td>2007</td><td>RS</td><td>60</td><td>218</td><td>4.5</td><td>92.4</td><td>Yes</td><td>DM2</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Molina et al<sup>23</sup></td><td>2010</td><td>CC</td><td>81</td><td>100</td><td>18</td><td>64.3</td><td>No</td><td>Cyclosporine</td><td>...</td><td>...</td><td>No</td></tr><tr><td>Jokinen et al<sup>24</sup></td><td>2010</td><td>RS</td><td>...</td><td>93</td><td>4</td><td>...</td><td>...</td><td>...</td><td>25</td><td>Yes</td><td>...</td></tr><tr><td>Delgado et al<sup>25</sup></td><td>2010</td><td>RS</td><td>81</td><td>1062</td><td>...</td><td>...</td><td>Yes</td><td>Age, Male</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Thomas et al<sup>26</sup></td><td>2012</td><td>RS</td><td>60</td><td>1495</td><td>3</td><td>72</td><td>Yes</td><td>Age, DM2, CHC, IRA</td><td>16.2</td><td>...</td><td>...</td></tr><tr><td>Samsky et al<sup>27</sup></td><td>2013</td><td>RS</td><td>60</td><td>454</td><td>5</td><td>...</td><td>...</td><td>...</td><td>...</td><td>...</td><td>Yes</td></tr><tr><td>Karamlou et al<sup>28</sup></td><td>2014</td><td>RS</td><td>...</td><td>26183</td><td>...</td><td>...</td><td>No</td><td>Age, DM2, AA, CIT</td><td>9</td><td>Yes</td><td>Yes</td></tr></tbody></table>

<footnote>*ESRD indicates end-stage renal disease; AKI, acute kidney injury; CKD, chronic kidney disease; CC, case-control; RS, retrospective; DM2, type 2 diabetes mellitus; ICM, ischemic cardiomyopathy; CHC, chronic hepatitis C; AA, African or African-American; and CIT, Cold ischemia time. Ellipses indicate not reported.</footnote>
cyclosporine), which represent the cornerstone
of immunosuppressive therapy in the setting of
transplantation, have been recurrently incriminated
as potent inductors of CKD in kidney and other
solid organ transplantation including heart
transplantation.¹⁹,²³ However, irrefutable evidence
of its nephrotoxicity is still lacking. In a study
including 18 kidney biopsy in heart transplant
recipients prompted by severe CKD (estimated
GFR, < 30 mL/min), the predominating histological
pattern was nephroangiosclerosis, present in all
cases. Features evocative of glomerulosclerosis
and focal segmental glomeruleosclerosis were
also found, albeit less consistently. Calcineurin
inhibitor toxicity was suspected in only 2 cases.⁴²

MANAGEMENT OF HEART TRANSPLANT
CANDIDATES

Nephrological Assessment Prior to Heart
Transplantation

Nephrological assessment may represent an
essential step for heart transplantation candidates
with an altered kidney function.⁴⁰ However, current
guidelines are rather laconic, to say the least, stating
proteinuria and renal artery ultrasonography as
the only warranted investigations in this setting.⁴³
Nevertheless, kidney biopsy should be contemplated
as it may provide crucial insights on the underlying
mechanisms behind the kidney disease, and
most of all, important cues on its prognosis. In a
study by Labban and coworkers performed on 30
patients with renal impairment precluding heart
transplantation by local standards (estimated
GFR, < 40 mL/min), details from kidney biopsy
histological analysis were found to be reassuring
in 14 cases thus clearing these patients for heart
transplantation.⁴⁴ As left ventricular dysfunction
is directly involved in the pathogenesis of CKD in
patients with heart failure, its reversal, through the
means of heart transplantation, may also benefit
the patient's kidney function. Following this line of
thought, a course of intravenous inotropic therapy
(phosphodiesterase III inhibitor) was performed
on patients awaiting heart transplantation in a
bid to simulate the effect of heart transplantation
and its potential benefit on kidney function. This
strategy may enable caregivers to identify patients
whose kidney function is the most likely to profit
from heart transplantation.¹⁴

When heart transplantation is not carried out, the

prospects for survival of patients with concurrent
advanced left ventricular dysfunction and CKD
are dim. For example, in a subgroup of patients
undergoing hemodialysis, Schaffer and colleagues
reported a 31% mortality within the 3 months
following inclusion on a heart transplantation
program.⁴⁵ A correlative finding was provided by
Samsky and associates who reported an acceptable
post-heart-transplantation rate (65% at 5 years) when
extending criteria for transplantation, including
lower GFR.²⁷

Combined Heart-Kidney Transplantation

Combined heart-kidney transplantation offers
another option when confronted with patients
with advanced heart failure together with renal
impairment precluding heart transplantation
alone. This strategy has been fast expanding even
though it is still a marginal procedure with only 50
or so transplantations carried out annually in the
United States.⁴⁰ Provided candidates for combined
heart-kidney transplantation are carefully selected,
this approach has yielded survival rates close to
that of single heart transplantation.²⁸,⁴⁶,⁴⁷ If the
limits of combined heart-kidney transplantation
remain elusive and even though guidelines on
patient selection have yet to be issued, recent
studies have unveiled several risk factors for poor
outcome including advanced recipient age ( > 65
years), peripheral vascular disease, nonischemic
cardiomyopathy, ESRD, and left ventricular
assistance.⁴⁸

Protecting Kidney Function Following Heart
Transplantation

Early posttransplantation stages. Management
in the early postoperative stages is of utmost
importance. Special care should be taken at
maintaining adequate renal perfusion and
avoiding nephrotoxic agents.⁴⁰ In the setting of
heart transplantation, this equates with restricting
contrast agent injections and calcineurin inhibitor
concentration monitoring. Calcineurin inhibitors
display a well-established acute nephrotoxic profile
mediated through renal arteriolar vasoconstriction
in a dose-dependent fashion.⁴⁹

Reducing the risk of immunosuppressor-related
nephrotoxicity. Numerous strategies have been
devised in order to mitigate the nephrotoxicity
associated with calcineurin inhibitors. These
include<sup>41,50</sup>: (1) delaying their introduction thanks to immunosuppressive induction therapy,<sup>50</sup> with either basiliximab<sup>51</sup> or thymoglobulin<sup>52,53</sup>, and (2) substituting anticalcineurin inhibitors for other immunosuppressors devoid of nephrotoxic effects; a pilot study involving 8 patients all of which manifested gradual renal impairment under calcineurin inhibitors showed stabilization or improvement of the kidney function in 7 cases once azathioprine and cyclosporine were switched to mycophenolate mofetil. In the same setting, everolimus and sirolimus, both mTOR inhibitors, once again used in as substitute immunosuppressors for calcineurin inhibitors, have been the focus of several small-scale studies yielding encouraging results.<sup>54-56</sup> Of note, mTOR inhibitors can only been contemplated after a protracted delay following transplantation as they may otherwise exert negative effects on wound healing.<sup>57</sup> Moreover, at least 1 study demonstrated an increased risk of acute rejection associated with the use of sirolimus.<sup>54</sup> Finally, recent experimental works indicate that sirolimus may induce glomerular proteinuria by interfering with the podocyte's cytoskeleton signalization and function, especially in the case of nephron reduction.<sup>58</sup>

## CONCLUSIONS

Chronic kidney disease represents a common issue and a major challenge among heart transplant recipients. If CKD portends a negative vital and renal outcome, it should not be regarded as an unsurmountable obstacle to heart transplantation. A multidisciplinary approach including a nephrological workup may help to better detect patients most likely to benefit from heart transplantation. In addition, several strategies allow extended access to heart transplantation, even in cases where patients display severely compromised kidney function. Among existing options, combined heart-kidney transplantation represents a promising approach.

## CONFLCIT OF INTEREST

None declared.

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Correspondence to:
Cédric Rafat, MD
Department of Renal Emergencies and Kidney Transplantation,
Hôpital Tenon, 4 rue de la Chine, 75020, Paris, France
Tel: +33 1 56 01 66 95
Fax: +33 1 56 01 79 68
E-mail: cedric.rafat@tnn.aphp.fr

Received December 2014