Cardiac and vascular changes with kidney transplantation.

Cardiovascular event rates are high in patients with chronic kidney disease (CKD), increasing with deteriorating kidney function, highest in CKD patients on dialysis, and improve with kidney transplantation (KTx). The cardiovascular events in CKD patients such as myocardial infarction and heart failure are related to abnormalities of vascular and cardiac structure and function. Many studies have investigated the structural and functional abnormalities of the heart and blood vessels in CKD, and the changes that occur with KTx, but the evidence is often sparse and occasionally contradictory. We have reviewed the available evidence and identified areas where more research is required to improve the understanding and mechanisms of these changes. There is enough evidence demonstrating improvement of left ventricular hypertrophy, except in children, and sufficient evidence of improvement of left ventricular function, with KTx. There is reasonable evidence of improvement in vascular function and stiffness. However, the evidence for improvement of vascular structure and atherosclerosis is insufficient. Further studies are necessary to establish the changes in vascular structure, and to understand the mechanisms of vascular and cardiac changes, following KTx.

Introduction

Cardiovascular changes related to chronic kidney disease (CKD) are common and a major cause of morbidity and mortality.[1] Large population-based studies have demonstrated a high incidence of cardiovascular events in the CKD patients, increasing with deteriorating renal function, with the highest rates in patients on dialysis.[2345]

Kidney transplantation (KTx) is associated with improvements in mortality due to cardiovascular events, namely myocardial infarction.[67] However, the risk is still high compared to the general population.[8]

The pathological changes in cardiac and vascular, structure and function in CKD are relatively well known, however, there is evidence that improvements occur following KTx and thus, may explain the reduced cardiovascular event rates in the transplanted population.[18]

The aim of this review is to summarize the changes in cardiac and vascular, structure, and function, with KTx, from the available evidence.

Methods

A literature search was conducted on PubMed using a generic search as well as a MESH term search involving the following prospective study, renal transplantation, CKD, echocardiography, left ventricular hypertrophy (LVH), left ventricular function, cardiac systolic function, cardiac diastolic function, pulse wave analysis, carotid intima-media thickness (CIMT), vascular endothelium, flow-mediated dilatation (FMD), endothelial function, endothelial dysfunction, endothelium, endothelial dependent dilatation, augmentation index (AIx), atherosclerosis, and arteriosclerosis.

The search results were then analyzed in order to select the prospective studies that explored any cardiac and vascular, structure and function, changes before and after renal transplantation.

Cardiac changes with kidney transplantation

Structure

There is ample evidence that the cardiac hypertrophy associated with CKD improves with KTx. Various echocardiographic studies have demonstrated such improvements in LVH with KTx. Table 1 lists the prospective studies of LVH in CKD patients undergoing KTx.

Table 1

Summary of studies showing changes in cardiac structure before and after KTx

The total numbers of patients included in the review of cardiac structural changes were 612 of which there were 63 children and 549 adults. The average ages spanned 8 ± 5 years in children to 47 ± 12 years in adults. The largest study was conducted by Rigatto et al. consisting of a prospective analysis of 143 patients and the smallest sample size was of 13 patients in three studies.[9131720]

In 11 out of the 15 studies, a significant reduction of mean LV mass index (LVMI) was noted after transplantation. The remaining four studies showed changes in LVH prevalence and LVMI but the differences were not significant.[121416] The greatest improvement in LVMI was noted by Himelman et al., with an average decrease of 55 g/m2 in 36 patients (P < 0.001).[18]

The change in LVMI was noted through a range of follow-up intervals after transplantation: As early as 3.2 ± 2.8 months and as late as 4 years postoperatively. Interestingly, in one long-term follow-up study, significant LVMI regression was observed only in the first 2 years after KTx and noted to plateau and stop beyond this time frame.[13] However, whether this trend is reflective of the general transplanted population and reproducible, remains to be seen. A major drawback of this study was that at 4 years posttransplantation, only 18 out of the 143 initial patients were available for follow-up echocardiograms.[13] Further long-term follow-up studies are, therefore, required in order to establish the potential course of LVH, years after transplantation.

The reduction in LVMI was predominantly significant for adults’ post-KTx. Although an average reduction in LVMI did occur in the studies focusing on children, in 2 out of the 3 studies, this change was not significant.[91112] This questions whether differences exist in the way hearts in children respond physiologically to the effects of a kidney transplant compared to adults.

It is unclear from the studies whether varying ages of adults influences the degree of change in LVMI. The study by Vaidya et al., explored 105 patients with a mean age of 54 years and showed a regression of 37.2 ± 31.3 g/m2 (P < 0.05) in 57 patients after transplantation.[19] In contrast, patients in the study by Ikäheimo et al. had a mean age of 31 years and showed a reduction of 54.2 ± 43.3 g/m2 in 13 patients (P < 0.001).[20] This could possibly indicate that with the exclusion of children and adolescent ages, the younger a CKD patient has a kidney transplant, the more the potential regression of the LVMI and LVH. These observations suggest more research is necessary to compare the LVMI change in younger versus older adults. The encouraging point, however, is that some degree of LVMI regression did occur irrespective of adult age.

Contrary to the above, rather than age, the length of follow-up time after transplantation may determine the degree of LVMI regression. McGregor et al. analyzed follow-up scans at an average of 4 months after KTx and found no significant difference between pretransplant and posttransplant LVMI.[16] However, Parfrey et al. analyzed patients with an average of 47 ± 23 months after transplantation and found that the LVMI improved from 166 ± 55 g/m2 to 135 ± 37 g/m2.[17] Another research avenue that could be explored is whether the more LVH one has at baseline is associated with greater regression post-KTx.

Function

There is reasonable evidence that shows improvement of cardiac function with KTx. Table 2 displays the prospective studies in adults and children demonstrating this change.

Table 2

Summary of studies showing changes in cardiac function before and after kidney transplantation

Similar to LVMI, most studies demonstrate significant improvement in both systolic and diastolic function in CKD patients following KTx.

There were 11 studies to our knowledge that described such changes following KTx. These comprised a total of 423 patients, including 29 children and 394 adults. The largest study was conducted by Parfrey et al. in whom 102 patients had their cardiac function assessed before and after KTx.[15] In comparison, the smallest study was undertaken by Sahagún-Sánchez et al. with 13 patients.[27]

A significant increase in LV ejection fraction (LVEF) posttransplantation was noted in 7 of the 11 studies. In addition, one study also demonstrated improvement in stroke volume.[16] There were four studies that showed a significant improvement in the fractional shortening after KTx.[11141527] Similarly, diastolic function had also been shown to improve following transplantation in four studies.[24262729]

The largest increase in systolic function was noted by Casas-Aparicio et al. who found that LVEF of the entire group of 35 patients had increased from 52% to 64% (P < 0.001) by 12 months after KTx.[26] In contrast, a study by Chammas et al., reported no significant change in LVEF in 32 patients at 28 ± 8 months post-KTx: The preoperative EF being 64% ± 5% and postoperative EF at 65% ± 4%.[28] Interestingly, however, in this same study by Chammas et al., there was also differing data on the diastolic function when compared with other studies. The group observed that a total of 6 patients out of 32 (19%) had diastolic dysfunction pretransplant, which decreased to five patients posttransplant. However, at 28 ± 8 months follow-up, diastolic dysfunction had increased to 7 out of 32 patients (22%).[28] Though the study suggests an improvement in diastolic function in the short-term with some deterioration long-term, overall data suggest an improvement in cardiac function. Of the two studies with the longest follow-ups, Hüting and Parfrey et al., showed significant improvements in LVEF of 5% and fractional shortening of 12%, respectively, 41–47 months after KTx.[1516]

Unlike the observation with cardiac structural changes, no difference was noted in cardiac function between studies conducted on children compared to those done on adults when assessing cardiac function, thus, indicating a general improvement across all ages.

In addition to this, no major variation or influence was seen objectively from the time of follow-up on systolic and diastolic function. Sharma et al. 2014 found that LVEF improved in 60 patients from 55% ± 9% to 64% ± 9% (P < 0.001) just 3 months after KTx.[25] In comparison, Hüting, who followed up patients at a mean time of 41 ± 30 months after renal transplantation, found that the LVEF increased from 58% ± 10% to 63% ± 12% (P < 0.02).[16] In fact, the degree of pre- to post-KTx improvement in LVEF was actually slightly smaller in patients who had echocardiograms after a longer follow-up period. Although this could be attributed to a number of factors such as hypertension and cardiac fibrosis due to immunosuppressive medications it needs further exploration with more careful research.

Vascular changes in structure and function with kidney transplantation

There have been a very limited number of prospective studies exploring changes in vascular structure in patients with CKD undergoing KTx. These are listed in Table 3.

Table 3

Summary of studies showing changes in vascular structure (CIMT) and function (PWV and AIx) before and after kidney transplantation

The CIMT, which is a reliable marker of atherosclerosis, was prospectively examined in two studies only. The total numbers of patients were 78 adults and follow-up intervals ranged from 3 months to 12 months posttransplant. Only one study showed a significant reduction in CIMT after KTx.

Caglar assessed CIMT in 42 patients before and 3 months after KTx. CIMT decreased from 8.52 ± 0.96 mm pretransplant to 5.96 ± 0.63 mm posttransplant (P < 0.001).[37] In contrast, Zoungas et al. assessed CIMT in 36 patients before and 12 months after KTx.[32] No significant difference in CIMT was noted between before, 0.76 ± 0.11 mm, and after, 0.75 ± 0.14 mm, transplantation. Lima et al. assessed CIMT in 22 patients, 12–20 weeks following KTx and found that CIMT fell from 0.79 ± 0.02 mm to 0.68 ± 0.03 mm (P < 0.01).[38] Although the study by Lima shows a significant reduction in CIMT, the baseline measurement was taken 2–3 weeks after KTx in contrast to the other two studies in which the measurement was taken before the transplant.

Hence, the convincing evidence is, therefore, lacking for vascular structural changes following KTx. There have, however, been various observational studies showing lower CIMT measurements in the kidney transplant population when compared to the CKD dialysis population.[394041] Thus, more carefully planned prospective studies are necessary to explore the changes in vascular atherosclerosis with KTx.

Arterial stiffness

The techniques used to measure arterial stiffness include measurement of arterial pulse wave velocity (PWV) and AIx. There have been a few studies that prospectively analyzed the effects of KTx on PWV in CKD patients [Table 3].

Our literature search found eight studies that prospectively assessed PWV before and after KTx. These studies encompassed a total of 237 patients of which 15 were children, and the remaining were 222 adults. The average age ranged from 11 ± 5 years in children to 46 ± 12 years in adults.

There were six studies that analyzed the AIx before and after KTx. These included a total of 151 patients, of which there were 15 children and 136 adults. Five out of these six studies showed a significant decrease in AIx post-KTx.[303132333536]

Seven studies showed a reduction in post-KTx PWV when compared to pretransplantation. However, five of these demonstrated a significant difference.[1032333435] Of the remaining two studies, both showed nonsignificant changes but one study actually showed an average increase in PWV after KTx.[3136]

The largest reduction in PWV post-KTx was observed by Kovács et al., who showed an average decrease of 5.1 m/s in 17 patients.[35] Kovács also showed a significant reduction of 48% in AIx posttransplantation from 42% ± 12% to 22% ± 12% (P < 0.05). Interestingly, this was also the study with the smallest patient size. Even more strikingly, this change was seen just 17 days after the transplantation. In contrast, the study with the longest follow-up time by Zoungas et al., showed a reduction in PWV of only 1.2 m/s, (P = 0.007) and a 33% reduction in AIx in 36 patients, 12 months after KTx.[32] In addition, the largest study by Hotta et al., conducted on 58 patients showed a reduction in PWV of 1.6 m/s (P < 0.01) at a follow-up period 6 months post-KTx.[34]

Only one of the seven studies looking at PWV involves children and when comparing this to the adult studies, a difference was noted. This study on 15 children, conducted by Aoun et al., observed an increase in PWV of 0.5 m/s after KTx; however, it was not found not to be significant. In addition, the change in AIx posttransplant was also not noted to be significant.[36] In contrast, every study on adults found a reduction in PWV posttransplantation. Due to lack of prospective PWV studies on children, we are unable to comment on whether really there is a difference between the changes in PWV in adults compared to children following KTx. This is, therefore, a potential for further research.

Endothelial function

Endothelial function assessment includes measuring endothelial dependent dilation either from analyzing brachial artery FMD or following angiography with acetylcholine infusion. Measurement of endothelial function has also be assessed by nitroglycerin induced dilatation (NID) and endothelial progenitor cell migration (EPC).

There is increasing evidence to show that the endothelial function improves following renal transplantation. Table 4 summarizes the changes in endothelial function in CKD patients following KTx.

Table 4

Summary of changes in endothelial function before and after kidney transplantation

There were eight studies found during the literature search that spanned across the years 2003–2014. In total, 383 patients were assessed, of which all were adults. The age range of patients varied from 25 ± 6 years to 40 ± 3 years. Follow-up intervals ranged from 14 days to 12 months after KTx. Out of the eight studies, seven assessed endothelial dependent dilation: Six with FMD and one with acetylcholine administration. The remaining study assessed endothelial function by analyzing EPC migration to mature endothelial cells. NID was assessed alongside five of the six FMD studies. The largest study was conducted by Yilmaz et al., who assessed a cohort of 161 patients.[42] In contrast, the smallest sample study was conducted by Passauer et al., in which eight patients were assessed.[45]

All eight studies showed some degree of improvement in endothelial function. In five out of six studies assessing FMD and three out of the five studies assessing NID, significant improvements were observed following KTx. In addition, the one study looking at endothelial dependent dilation via acetylcholine administration also showed a significant improvement after KTx.[45] Finally, KTx was also found to increase EPC migration by approximately two-fold.[43]

One of the biggest changes in FMD was observed by Sharma et al., in which 60 Indian patients were assessed before and 3 months after KTx.[25] The study showed an improvement in FMD from 9.1% to 15.7% following KTx. In addition, impaired FMD, defined as FMD <4.5%, was present in 26.8% of CKD patients pretransplant and 3.3% of patients posttransplant.[25] Thus, indicating that KTx can reverse endothelial dysfunction in CKD patients. Interestingly, however, there was no significant improvement in NID in the cohort of 60 patients posttransplantation. In contrast, the opposite was observed in a study by Hornum et al. in which both FMD and NID were assessed in 40 hemodialysis patients. The study found that NID improved significantly from 11% to 18% posttransplant; however, no significant difference was noted in the FMD.[31] Reasons for the variations in observations are difficult to explain but could be due to varied sample sizes and differences in patient characteristics.

Comparatively, the study by Yilmaz et al. was conducted on a larger sample of 161 chronic hemodialysis patients receiving KTx. At 6 months posttransplant, there was a significant improvement of 1.4% in FMD from 5.2% ± 0.8% to 6.6% ± 0.8% (P < 0.001) as well as a significant improvement of 0.6% in NID from 11.9% ± 0.9% to 12.5% ± 0.7% (P < 0.001).[42] In addition to improved vascular function, this study also showed a parallel improvement in the FGF23, serum phosphorus, and 25 (OH) Vitamin D levels. Thus, highlighting a potential link between improvement of CKD-mineral bone disease and reduction in cardiovascular risk.[42]

The study with the shortest follow-up time was conducted by Kocak et al., who assessed FMD in 30 patients 3 days before and 14 days after KTx. The study found a 57% improvement in FMD, from 6.7% to 10.5%, posttransplantation (P < 0.001).[46] In comparison, Oflaz et al. followed up patients both at 6 months and 12 months after KTx. The study found that FMD improved from baseline (5.6%) at both 6 months (8.3%) and continued to improve at 12 months (12.1%).[44] Hence, a total improvement of 116% posttransplantation. This indicates that KTx potentially result in a sustained improvement in FMD and thus, improve atherosclerosis in long-term, which needs further research.

An interesting question is whether there is a difference in endothelial function between the preemptive and dialysis patients, post-KTx. Sharma et al. found that CKD patients with GFR of <15 had poorer average FMD (8.8%) compared with those patients who had a GFR of 15–60 ml/min/1.73 m2 (12.9%).[25] Potential research could, therefore, help identify whether KTx has a more beneficial effect on endothelial function in predialysis versus dialysis patients.

Finally, no prospective studies assessing endothelial function in children were found during our literature search. This is another area for further research in order to establish the effect of KTx on endothelial function in children.

Risk factors and pathophysiology

The heightened cardiovascular event rates in the CKD population have been predominantly attributed to atheromatous and nonatheromatous vascular disease. Traditional risk factors, though frequently present do not fully explain this increased risk in the CKD population. Interestingly, the nontraditional risk factors such as inflammation, oxidative stress, abnormalities of calcium, phosphate and PTH balance, as well as Vitamin D deficiency and anemia are increasingly being recognized as causes of the high cardiovascular event rates.[47]

The vascular changes related to the improvement in uremic milieu are not very well known, however, may be attributed to improvements in the inflammatory profile. Inflammation contributes to chronic dysregulation of nitric oxide in vascular smooth muscle, and hence, results in endothelial dysfunction; the consequence of which is vessels being at risk of becoming proatherogenic.[4849] Down regulation of inflammatory pathways and intercellular adhesion molecules responsible for the endothelium-leukocyte interaction, could contribute to the improved nitric oxide generation and endothelial function following KTx.

LVH is caused by inflammation, fibrosis, and increased afterload. In addition, anemia and fluid overload results in left ventricular dilation with LVH and the resulting structural abnormalities contribute to both systolic and diastolic dysfunction.[50] A large proportion of the studies discussed in this review show regression of LVH and improvement of cardiac function following KTx. More recent research has found a relationship between endothelial dysfunction and LVH.[51] We propose that improvement in LVH may be related to improvement in endothelial dysfunction.

Conclusion

There is substantial evidence to show that KTx results in a reduction in LVH. There is some evidence to suggest an improvement of cardiac function in CKD patients following KTx. There is a lack of prospective research assessing the effect of KTx on vascular structure, especially CIMT. There is increasing evidence describing the improvement of endothelial function in CKD patients following KTx in adults; however, further research is required in children.

This review highlights the changes in cardiovascular structure and function following KTx; however, further research is necessary to establish the vascular changes, as well as to investigate the mechanisms behind these changes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.