Özet

Background: In this study, we aimed to investigate the mid-term effects of left ventricular assist devices on kidney functions.

Methods: Between January 2015 and December 2017, a total of 61 patients (53 males, 8 females; mean age 46.4±11.2 years; range, 20 to 67 years) who underwent left ventricular assist device implantation were retrospectively analyzed. Glomerular filtration rate was evaluated preoperatively and at 24 and 48 h, at one week, and at one, three, and six months postoperatively. According to the preoperative glomerular filtration rates, the patients were divided into three groups: glomerular filtration rates ?60 mL/min/1.73 m2 ( Group 1 ), g lomerular f iltration rates 61-90 mL/min/1.73 m2 (Group 2), and glomerular filtration rates >90 mL/min/1.73 m2 (Group 3).

Results: In all groups, the glomerular filtration rate significantly increased at one week and one month postoperatively, compared to preoperative values (p<0.001 and p<0.01, respectively). However, the glomerular filtration values at six months significantly decreased, compared to the values at one week and one month postoperatively (p<0.001 and p<0.001, respectively). The most significant drop to preoperative values was observed in Group 3 (p=0.02) at three months and it dropped below the preoperative level at six months (p<0.001).

Conclusion: Our study results suggest that left ventricular assist devices can significantly increase the glomerular filtration rate in short-term, irrespective of baseline values. However, this improvement may recede later, particularly in patients with normal renal functions, and it may even disappear following the third postoperative month.

The number of patients with end-stage heart failure (HF) has been increasing over time. A left ventricular assist device (LVAD) implantation has been preferred more frequently for the treatment of medical therapy-resistant end-stage HF patients, owing to improved success rates over the last three decades.[1] The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) study showed that patients receiving LVAD for end-stage HF had two-fold oneyear survival rates, compared to those receiving optimal medical therapy.[2] These devices are frequently used to bridge-to-transplantation for end stage HF and, as outcomes are promoted with the improvements in patient care and technology, a trend toward destination therapy arises over the years for those who are ineligible for the transplantation.

End-stage HF is often associated with renal insufficiency. Additionally, factors such as high right atrial pressure, adverse neuroendocrine regulation, and high dose of diuretics contribute to renal failure.[3] Renal failure a ccompanied by HF (cardio-renal syndrome Type 2) is a mediator of worse outcome.[4] Given the fact t hat LVAD s upport has apparent cardiac therapeutic effects, preoperative renal status of the patient must be considered during the decision-making process prior to implantation.[5] Furthermore, the decision of post-LVAD treatment option (destination therapy or heart transplantation [HTx]) also depends on the patient"s renal reserve, which guides our postoperative strategy.

In this study, we aimed to investigate the mid-term effects of LVAD therapy on kidney functions in endstage HF patients.

Yöntem

Between January 2015 and December 2017, a total of 87 patients with intractable end-stage HF underwent LVAD implantation at Kartal Kosuyolu Heart Training and Research Hospital. Twenty-six patients were excluded from the study due to a short duration of survival than six months or included in HTx before the postoperative six months. Finally, 61 patients (53 males, 8 females; mean age 46.4±11.2 years; range, 20 to 67 years) who received more than six-month LVAD support were included in this retrospective study. The study protocol was approved by the institutional Ethics Committee of Kartal Koşuyolu Yüksek İhtisas Training and Research Hospital. The study was conducted in accordance with the principles of the Declaration of Helsinki.

Demographic data, left ventricular ejection fraction (LVEF), type of LVAD implanted, preoperative use of inotropic agents, preoperative intra-aortic balloon pump (IABP) insertion, and perioperative laboratory test results were recorded. The glomerular filtration rate (GFR) which was calculated using the Modification of Diet in Renal Disease formula {eGFR (mL/min/1.73 m²) = 175 ¥ [serum creatinine (mol/L) ¥ 0.0113]-1.154 ¥ age (years)-0.203 (¥ 0.742 if female)} was used to evaluate renal functions before and after surgery. According to the preoperative GFR values, the patients were divided into three groups: GFR ?60 mL/min/1.73 m² (Group 1), GFR 61-90 mL/min/1.73 m² (Group 2), and GFR >90 mL/min/1.73 m² (Group 3). Renal functions after LVAD implantation were evaluated preoperatively and at 24 and 48 h, at one week, and at one, three, and six months postoperatively. Intra- and inter-group assessment was performed for postoperative course of renal insufficiency.

Statistical analysis
Statistical analysis was performed using the SPSS version 15.0 software (SPSS Inc., Chicago, IL, USA). Descriptive data were expressed in mean ± standard deviation (SD), median (min-max), interquartile range, or number and frequency. Continuous random variables were compared using the one-way analysis of variance (ANOVA) with the Tukey post-hoc test or Kruskal-Wallis ANOVA with the Dunn's post-hoc test between the groups according to the data distribution (normally or non-normally distributed), while intra-group analysis was performed using the repeated measures of ANOVA with the Tukey Kramer post-hoc test or Friedman test with the Dunn's post-hoc test. For the categorical random variables, the chi-square test was used. A new variable, namely percent of change, was calculated between the preoperative values and postoperative values at 24 and 48 h, at one week, and at one, three, and six months and, then, one-way ANOVA was used to compare these new variables between the groups. A p value of <0.05 was considered statistically significant.

Bulgular

Demographic data are shown in Table 1. The leading etiology of HF was dilated cardiomyopathy. Right ventricular functions were relatively preserved, despite impaired LV functions in all patients. More than two-thirds of the patients needed inotropic support preoperatively and IABP-support was applied for hemodynamic stabilization in six patients in Group 2 and eight patients in Group 3. All patients were under diuretic therapy without the need for renal replacement therapy (RRT) preoperatively. All patients following LVAD implantation needed inotropic support (mostly dobutamine and noradrenaline) with/without pulmonary vasodilator (nitric oxide and/or iloprost) and were under renal dopamine infusion. None of the patients needed IABP support. The main strategy was to maintain adequate cardiac output (CO) to prevent right heart failure and to avoid anemia, hypoalbuminemia, and hyponatremia. During the postoperative follow-up, seven patients (n=4 in Group 1 and n=3 in Group 3) developed reversible acute renal failure and required RRT. Two patients needed transient RRT and post-discharge kidney functions returned to normal. The other five patients required continuous RRT during their intensive care unit stay, and the causes of death were sepsis (n=2), cerebrovascular accident, device malfunction (n=1), and cardiac cirrhosis (n=1).

Table 1. Demographic data of patients

After LVAD implantation, statistically significant GFR changes were observed in the all groups at specific time points: (i) a statistically non-significant decrease was observed at the first day after LVAD implantation during the first change-period; (ii) a statistically significant increase progressed after the second postoperative day and reached the peak level at the first week during the second change-period; (iii) the third change-period was drawing a plateau in the improvement, until the first postoperative month; and (iv) an impairment followed by regression to preoperative levels was observed at six months during the fourth change-period (Figure 1).

Figure 1. Glomerular filtration rate changes at specified time points after LVAD implantation.
GFR: Glomerular filtration rate; LVAD: Left ventricular assist device; * First change period (regression within the first 24 h);
** Second change period (progression after 48 h); *** Third change period (accession and stabilization between the first week and first month); **** Fourth change period (retrogression and retrocession after the first month)
Dash-line indicates alteration trend in postoperative GFR-response to LVAD within the first six months.

The improvement in renal function showed a concave curve, indicating a significant rebound from a statistical improvement to the baseline level. Therefore, the increase in the postoperative mean GFRs at one week and one month showed a statistically significant improvement, compared to preoperative GFR values, whereas the decrease in the postoperative mean GFR at six months showed a statistically significant decline, compared to increased postoperative GFR values at one week and one month in the all groups (Table 2).

Table 2. Glomerular filtration rate changes at specified time points

The comparison of subgroups showed several significant changes (Figure 2). The patients of all groups suffered from a slight decline in the mean postoperative GFR values immediately after surgery, particularly during the first 48 h. This time point was passed to stabilize the patients postoperatively, particularly to prevent bleeding and to adjust hemodynamic instability, intravascular volume reduction, and tissue hypoperfusion. Following the prospering management, a significant increase in the mean postoperative GFR was observed in all three groups during the first week postoperatively and achieved to peak levels in Groups 2 and 3 at one week and Group 1 at one month. As a consequence, the increase in the mean postoperative GFR began to decrease after reaching the peak level at one month in Group 1 and at one week in the Group 3. However, the increase in the mean postoperative GFR of Group 2 was reserved during the first postoperative month after reaching the peak level at one week and began to decrease afterwards. The first two groups had still higher mean GFR values at six months postoperatively, compared to preoperative levels and Group 3 showed a negative progress by impaired postoperative GFR values below the preoperative ones.

Figure 2. Glomerular filtration rate changes at specified time points after LVAD implantation.
Group 1: GFR ?60 mL/min; Group 2: GFR 61-90 mL/min; Group 3: GFR >90 mL/min; GFR: Glomerular filtration rate; LVAD: Left ventricular assist device; SD: Standard deviation; Min: Minimum; Max: Maximum.

More interestingly, the first two groups continued to show an improvement until the sixth postoperative month, whereas Group 3 showed the very opposite case by reduction of postoperative GFR below the preoperative levels (Table 3). As a result, the first two groups showed a higher increase ratio in median percent of changes in GFR values between preoperative and at three months postoperatively (22.8% and 16.1%, respectively), compared to Group 3 (-2.3%). However, this decline back to baseline values in Group 3, reaching a statistical significance only in Group 1 at three months (p=0.02). The median and mean GFR values in Group 3 dropped below the preoperative levels at six months postoperatively. The median percent of change in GFR between preoperative and postoperative values at six months remained higher in Groups 1 and 2 (11.5% and 13.3%, respectively), compared to Group 3 (-1.3%). This decline reached a statistical significance in the other two groups (p=0.001).

Table 3. Glomerular filtration rate percent of change values at specified time points

Tartışma

In the present study, we evaluated the changes in renal function by calculating pre- and postoperative GFR values after LVAD implantation in the patients who suffered from end-stage HF with or without renal insufficiency, addressing into the effect of improvement in cardiac functions by LVAD on renal functions. A significant alteration wave in the postoperative GFR is the main finding of this study. An initial mild decrease in GFR at the first postoperative day was followed by a progressive and statistically significant increase during the first postoperative week. The improved GFR started to decline after the third postoperative month and to regress to the baseline values at the end of six months. The second finding is that temporary improvement of LVAD implantation on renal functions, irrespective of patients' demographic, clinical, and biochemical properties, varied according to preoperative GFR values. Group 1 including patients with the lowest preoperative GFR showed the most evident increase during the first postoperative month and had still a remarkable increase at six months. This was also observed in Group 2. The third and, maybe the most important result, is that patients without any preoperative renal damage were unable to get any benefit from the beneficial effect of LVAD on renal functions. However, continuous arterial flow might have affected normo-functional kidneys adversely during mid-term follow-up.

Although many studies have indicated a significant improvement in renal functions and a considerable recovery in preoperative renal insufficiency in endstage HF patients after LVAD implantation, a precise mechanism for this improvement has not been demonstrated.[6-9] Renal failure is the strongest indicator of postoperative mortality. Therefore, in patients with dialysis-dependent renal insufficiency or in patients with creatinine >5 mg/dL, mechanical support device implantation is relatively contraindicated, but mild and moderate renal disorders are improved by LVAD implantation.[10] This improvement in renal functions may develop in all patient groups after LVAD implantation, regardless of preoperative renal insufficiency degree.[11] Theoretically, an increase in CO after LVAD implantation is expected to improve renal perfusion and renal function.[12] This recovery usually occurs in the first month of LVAD implantation and remains stable for up to one year.[13,14] Despite positive mid-term benefits of LVAD implantation on renal functions, longterm effects of LVAD implantation (one to three years) is frustrating with regression of postoperative increased GFR values to preoperative values.[15,16] In addition, the degree of renal improvement after LVAD implantation is also related to preoperative GFR values. Several studies with subgroups formed by the severity of renal dysfunction showed that the worst subgroups with the lowest GFR values ended up with the most optimal renal improvement results after LVAD implantation.[12,14,17] It is reasonable to conclude that the cumulative effect of various mechanisms contributes to short-term renal improvement. The first mechanism may be the regulation of intra-renal hemodynamics after providing sufficient distal perfusion via balanced CO by LVAD support.[18] Secondly, the activity of the renin-angiotensin-aldosterone system (RAAS) diminishes within four to eight weeks after LVAD implantation.[19] Thirdly, sympathetic activity on the renal system becomes evident due to cardiopulmonary and aortic baroreceptor regulation, which results in decreased renal vascular resistance.[5,20] Finally, plasma epinephrine and norepinephrine levels reduce after LVAD implantation.[21]

The possible mechanism of GFR regression after LVAD implantation during long-term follow-up can be the hypertrophy of smooth muscles at renal arteries with an increase in collagen and decrease in elastin components in the aortic wall after long-term support by LVAD with the continuous flow.[22,23] This long-term, anti-physiological support causes severe periarteritis in kidneys and provokes the upregulation of RAAS in inflammatory cells due to loss of pulsatility in the systemic arterial circulation.[24] Another possible reason can be the development of renal tubular necrosis due to chronic hemolysis of blood components during long-term LVAD support. On the other hand, any right heart failure caused by elevated central venous pressure due to excessive left ventricle unloading or volume overload should not be ignored due to impairment of renal arterial circulation by renal venous congestion, i.e., inadequate renal perfusion and, consequently, deterioration in renal functions.[25]

In our study, a significant increase in GFR progressed after the second postoperative day in the all groups, and the highest peak level was reached at the first postoperative week. After reaching the peak level, this increase was stabilized until the first postoperative month; however, it could not be preserved and decline was started back to preoperative levels. However, postoperative GFR remained slightly elevated at six months and, in some, thereafter. The most interesting finding is that this negative reversal was most evident in Group 3, in which the mean postoperative GFR declined to the baseline level at three months postoperatively, earlier than the other two groups. Our study showed that the preoperative renal insufficiency degree was the only factor affecting the postoperative renal response. The regression of the improved GFR was limited in Groups 1 and 2, and this improvement still continued until the sixth postoperative month and, probably, thereafter. Only Group 3 showed a negative progress after the third postoperative month. The reason for this inverse wave movement may be the continuous arterial flow by LVADs, which affects renal cellular response adversely, and increased CO cannot further improve normal kidneys after surgery. However, we should keep in mind that the reduction of GFR in Group 3 does not exceed the preoperative GFR values. As the trend line of Group 3 indicates, the ideal period for HTx in this group may be the first month postoperatively. However, in this group of patients, there is no limited time for HTx due to the normal function of the kidneys. Group 2 patients with mild-to-moderate renal insufficiency showed a peak improvement at the first postoperative week and a durable improvement in GFR during the first postoperative month, which continued with a slight decline until the third postoperative month and, probably, thereafter. This group of patients suffered from inadequate renal perfusion due to lower CO preoperatively and benefits from balanced CO by LVADs to provide further improvement in renal function postoperatively, particularly for the first three postoperative months. These patients may be treated first with LVADs to bridge to HTx with the goal of improvement in renal function before HTx and the reduction of adverse effects of immunosuppressive therapy on kidneys after HTx. As the trend line of Group 2 indicates, the ideal period for HTx in this group may spread within the first three months postoperatively. In our study, Group 1 patients with the lowest GFR preoperatively showed the highest improvement in GFR with a percentage of 56% at one month after LVAD support, which continued with a slight decline until the sixth postoperative month. This group of patients may have temporary or permanent primary or secondary kidney injury, and recovery probability of renal failure must be showed via balanced CO by LVAD to decide single or dual organ transplantation before HTx. As the trend line of Group 1 indicates, the ideal time for HTx in this group may begin after the first month and sustain until the sixth month postoperatively.

Currently, more end-stage HF patients expect HTx to hold on to life with LVAD therapy, and we hope that adverse effects of non-physiological circulation caused by LVADs can be improved with newly developed devices including physiological circulation dynamics. Perhaps the most promising aspect of these devices is that a significant improvement in preoperatively impaired renal function can make these patients more suitable for isolated HTx than dual (heart+kidney) transplantation. On the other hand, new devices with more kidney-protective effects may provide a new life chance for end-stage HF patients who are considered ineligible for HTx due to impaired renal functions.

The main limitation is the retrospective design of this study. Another limitation is that the number of patients evaluated for kidney function during follow-up was relatively low, as we were unable to include every lost patient or patients undergoing HTx before six months after LVAD implantation not to contort the analyses. The number of patients in each group limited our ability to distinguish differences among the groups and to investigate subgroup differences; however, most patients with impaired renal function was not included in HTx program and as well as LVAD program.

In conclusion, to benefit from left ventricular assist device implantation, optimization of the kidney-related outcomes of left ventricular assist device therapy should be tailored to the appropriate patient population by evaluating perioperative hemodynamic, physiological, pathological, and clinical characteristics. End-stage heart failure patients with preoperative renal insufficiency must be directed first to left ventricular assist device therapy to investigate any opportunity to be a candidate for isolated heart transplantation rather than for heart and renal transplantation, and additionally, to improve renal function before heart transplantation. Probably, it would be better to keep compensated end-stage heart failure patients with normo-function kidneys away from left ventricular assist device therapy until heart transplantation.

Declaration of conflicting interests
The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding
The authors received no financial support for the research and/or authorship of this article.

Kaynaklar

1) Jeevanandam V. The evolution of cardiac assist device technology. J Heart Lung Transplant 2010;29:11-2.

2) Rose EA, Gelijns AC, Moskowitz AJ, Heitjan DF, Stevenson LW, Dembitsky W, et al. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med 2001;345:1435-43.

3) Hillege HL, Girbes AR, de Kam PJ, Boomsma F, de Zeeuw D, Charlesworth A, et al. Renal function, neurohormonal activation, and survival in patients with chronic heart failure. Circulation 2000;102:203-10.

4) Forman DE, Butler J, Wang Y, Abraham WT, O"Connor CM, Gottlieb SS, et al. Incidence, predictors at admission, and impact of worsening renal function among patients hospitalized with heart failure. J Am Coll Cardiol 2004;43:61-7.

5) Mao H, Katz N, Kim JC, Day S, Ronco C. Implantable left ventricular assist devices and the kidney. Blood Purif 2014;37:57-66.

6) Farrar DJ, Hill JD. Recovery of major organ function in patients awaiting heart transplantation with Thoratec ventricular assist devices. Thoratec Ventricular Assist Device Principal Investigators. J Heart Lung Transplant 1994;13:1125-32.

7) Russell SD, Rogers JG, Milano CA, Dyke DB, Pagani FD, Aranda JM, et al. Renal and hepatic function improve in advanced heart failure patients during continuous-flow support with the HeartMate II left ventricular assist device. Circulation 2009;120:2352-7.

8) Kamdar F, Boyle A, Liao K, Colvin-adams M, Joyce L, John R. Effects of centrifugal, axial, and pulsatile left ventricular assist device support on end-organ function in heart failure patients. J Heart Lung Transplant 2009;28:352-9.

9) Butler J, Geisberg C, Howser R, Portner PM, Rogers JG, Deng MC, et al. Relationship between renal function and left ventricular assist device use. Ann Thorac Surg 2006;81:1745-51.

10) Küçükaksu DS, Şener E, Taşdemir O. Bridging the heart transplantation with mechanical systems: patient and device selection. Turk Gogus Kalp Dama 2002;10:190-200.

11) Singh M, Shullo M, Kormos RL, Lockard K, Zomak R, Simon MA, et al. Impact of renal function before mechanical circulatory support on posttransplant renal outcomes. Ann Thorac Surg 2011;91:1348-54.

12) Patel AM, Adeseun GA, Ahmed I, Mitter N, Rame JE, Rudnick MR. Renal failure in patients with left ventricular assist devices. Clin J Am Soc Nephrol 2013;8:484-96.

13) Demirozu ZT, Etheridge WB, Radovancevic R, Frazier OH. Results of HeartMate II left ventricular assist device implantation on renal function in patients requiring postimplant renal replacement therapy. J Heart Lung Transplant 2011;30:182-7.

14) Daimee UA, Wang M, Papernov A, Sherazi S, McNitt S, Vidula H, et al. Renal Function Changes Following Left Ventricular Assist Device Implantation. Am J Cardiol 2017;120:2213-20.

15) Yoshioka D, Takayama H, Colombo PC, Yuzefpolskaya M, Garan AR, Topkara VK, et al. Changes in End-Organ Function in Patients With Prolonged Continuous-Flow Left Ventricular Assist Device Support. Ann Thorac Surg 2017;103:717-24.

16) Hasin T, Topilsky Y, Schirger JA, Li Z, Zhao Y, Boilson BA, et al. Changes in renal function after implantation of continuous-flow left ventricular assist devices. J Am Coll Cardiol 2012;59:26-36.

17) Slaughter MS, Rogers JG, Milano CA, Russell SD, Conte JV, Feldman D, et al. Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med 2009;361:2241-51.

18) Iwashima Y, Yanase M, Horio T, Seguchi O, Murata Y, Fujita T, et al. Effect of pulsatile left ventricular assist system implantation on Doppler measurements of renal hemodynamics in patients with advanced heart failure. Artif Organs 2012;36:353-8.

19) James KB, McCarthy PM, Jaalouk S, Bravo EL, Betkowski A, Thomas JD, et al. Plasma volume and its regulatory factors in congestive heart failure after implantation of long-term left ventricular assist devices. Circulation 1996;93:1515-9.

20) Yambe T, Nitta S, Katahira Y, Sonobe T, Tanaka M, Miura M, et al. Effect of left ventricular assistance on sympathetic tone. Int J Artif Organs 1990;13:681-6.

21) James KB, McCarthy PM, Thomas JD, Vargo R, Hobbs RE, Sapp S, et al. Effect of the implantable left ventricular assist device on neuroendocrine activation in heart failure. Circulation 1995;92:191-5.

22) Kihara S, Litwak KN, Nichols L, Litwak P, Kameneva MV, Wu Z, et al. Smooth muscle cell hypertrophy of renal cortex arteries with chronic continuous flow left ventricular assist. Ann Thorac Surg 2003;75:178-83.

23) Ambardekar AV, Hunter KS, Babu AN, Tuder RM, Dodson RB, Lindenfeld J. Changes in Aortic Wall Structure, Composition, and Stiffness With Continuous-Flow Left Ventricular Assist Devices: A Pilot Study. Circ Heart Fail 2015;8:944-52.

24) Ootaki C, Yamashita M, Ootaki Y, Kamohara K, Weber S, Klatte RS, et al. Reduced pulsatility induces periarteritis in kidney: role of the local renin-angiotensin system. J Thorac Cardiovasc Surg 2008;136:150-8.

25) Tromp TR, de Jonge N, Joles JA. Left ventricular assist devices: a kidney's perspective. Heart Fail Rev 2015;20:519-32.