Progression of Coronary Artery Calcification and Thoracic Aorta Calcification in Kidney Transplant Recipients

doi:10.1053/j.ajkd.2011.07.019

American Journal of Kidney Diseases

Volume 59, Issue 2, February 2012, Pages 258-269

https://doi.org/10.1053/j.ajkd.2011.07.019 Get rights and content

Background

Vascular calcification independently predicts cardiovascular disease, the major cause of death in kidney transplant recipients (KTRs). Longitudinal studies of vascular calcification in KTRs are few and small and have short follow-up. We assessed the evolution of coronary artery (CAC) and thoracic aorta calcification and their determinants in a cohort of prevalent KTRs.

Study Design

Longitudinal.

Setting & Participants

The Agatston score of coronary arteries and thoracic aorta was measured by 16-slice spiral computed tomography in 281 KTRs.

Predictors

Demographic, clinical, and biochemical parameters were recorded simultaneously.

Outcomes & Measurements

The Agatston score was measured again 3.5 or more years later.

Results

Repeated analyzable computed tomographic scans were available for 197 (70%) KTRs after 4.40 ± 0.28 years; they were not available for the rest of patients because of death (n = 40), atrial fibrillation (n = 1), other arrhythmias (n = 4), refusal (n = 35), or technical problems precluding confident calcium scoring (n = 4). CAC and aorta calcification scores increased significantly (by a median of 11% and 4% per year, respectively) during follow-up. By multivariable linear regression, higher baseline CAC score, history of cardiovascular event, use of a statin, and lower 25-hydroxyvitamin D₃ level were independent determinants of CAC progression. Independent determinants of aorta calcification progression were higher baseline aorta calcification score, higher pulse pressure, use of a statin, older age, higher serum phosphate level, use of aspirin, and male sex. Significant regression of CAC or aorta calcification was not observed in this cohort.

Limitations

Cohort of prevalent KTRs with potential survival bias; few patients with diabetes and nonwhites, limiting the generalizability of results.

Conclusion

In contrast to previous small short-term studies, we show that vascular calcification progression is substantial within 4 years in prevalent KTRs and is associated with several traditional and nontraditional cardiovascular risk factors, some of which are modifiable.

Section snippets

Patients

The prevalent Brussels Renal Transplant Cohort was initiated from February 3, 2004, to January 27, 2005. All KTRs with a functional transplant for 1 year or longer attending the outpatient clinic of the Cliniques universitaires Saint Luc (Brussels) for their annual or biannual in-depth control were asked to enter the study. The protocol was approved by the Ethics Committee of the Cliniques universitaires Saint Luc Medical School, and written informed consent was obtained from all patients.

Study Cohort

Of the initial 281 patients in the cohort, 40 died before the appointment for the second CT; one had atrial fibrillation, thus precluding a successful scan; and 35 declined to undergo the second CT. Therefore, 205 patients underwent repeated CT after 4.40 ± 0.28 years. Calcium scoring could not be performed in 8 of these patients because of technical problems (n = 4) or arrhythmias (n = 4). Thus, the study cohort included 197 patients (Fig 1). Patients resuming dialysis therapy (n = 14) were

Discussion

To our knowledge, the present study is the first to assess the progression of both CAC and aorta calcification in a large population of stable KTRs with a relatively long follow-up. Our major finding is that vascular calcification progresses substantially within 4 years in prevalent KTRs: CAC increased by a median of 11% per year and aorta calcification increased by a median of 4% per year in KTRs with a baseline vascular score >30 mg.²¹ In 25% of patients, the yearly increase in CAC and aorta

Acknowledgements

The authors acknowledge Y. Pirson and members of the Cliniques universitaires Saint Luc Nephrology Collaborative group for careful joint follow-up of patients, Alain Vlassenbroek from Philips Healthcare for the thoracic CT, and Prof. W. Jahnen-Dechent for the gift of the anti-fetuin A antibody.

Support: This study received financial support from the Fonds National de la Recherche Scientifique Médicale, the Fondation Saint-Luc, the EU project grant GENECURE (FP6 LSHM CT 2006 037697), the

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Cited by (81)

Prognostic Value of Pre- and Post-Serum Alkaline Phosphatase Among Renal Transplant Recipients
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Recent studies have shown that high levels of serum alkaline phosphatase (ALP) are associated with all-cause and cardiovascular death among patients undergoing hemodialysis. However, there is limited knowledge on the effect of ALP level in kidney transplant recipients (KTRs). The aim of this study was to evaluate if serum ALP levels before and after transplant and the changes in ALP levels are associated with graft failure and mortality.
Between January 1997 and December 2012, 3029 KTRs were enrolled in a multicenter cohort. We examined the association of pre- and posttransplant serum ALP levels and long-term outcomes in KTRs.
Pretransplant serum ALP level >80 IU/L was associated with a hazard ratio (HR) for graft failure of 1.571 in a fully adjusted model. The graft failure rate gradually increased with ALP level increments of 20 IU/L in KTRs with ALP levels >60 IU/L. An increase in serum ALP level by 40 IU/L during the first 3 months after kidney transplant was associated with higher rates of graft failure (HR, 2.353) and higher rates of mortality (HR, 2.733).
Elevated pre-and posttransplant serum ALP levels and increases in the serum ALP levels after kidney transplant increase the risk of graft failure and mortality among KTRs.
Computed tomography of the aorta
2022, Textbook of Arterial Stiffness and Pulsatile Hemodynamics in Health and Disease
Computed tomography angiography (CTA) technology has witnessed immense improvements through the last decade. With the appearance of the new generation of scanners (multidetector computed tomography), CTA has become the preferred tool for imaging the heart, great vessels, and the vascular tree. The power of the CTA in aortic imaging lies in its ability to provide detailed accurate information within seconds about the anatomy, geometry, and various pathologic conditions in the whole length of the vessel in a noninvasive way.
Changes of the aorta with aging and disease can be detected with CTA. In particular, computed tomography is an excellent technique to quantify aortic wall calcification, which leads to aortic stiffening. It can also quantify geometric changes related to aging (such as elongation and tortuosity) which interact with aortic wall stiffening to impact central hemodynamics.
The ViKTORIES trial: A randomized, double-blind, placebo-controlled trial of vitamin K supplementation to improve vascular health in kidney transplant recipients
2021, American Journal of Transplantation
Premature cardiovascular disease and death with a functioning graft are leading causes of death and graft loss, respectively, in kidney transplant recipients (KTRs). Vascular stiffness and calcification are markers of cardiovascular disease that are prevalent in KTR and associated with subclinical vitamin K deficiency. We performed a single-center, phase II, parallel-group, randomized, double-blind, placebo-controlled trial (ISRCTN22012044) to test whether vitamin K supplementation reduced vascular stiffness (MRI-based aortic distensibility) or calcification (coronary artery calcium score on computed tomography) in KTR over 1 year of treatment. The primary outcome was between-group difference in vascular stiffness (ascending aortic distensibility). KTRs were recruited between September 2017 and June 2018, and randomized 1:1 to vitamin K (menadiol diphosphate 5 mg; n = 45) or placebo (n = 45) thrice weekly. Baseline demographics, clinical history, and immunosuppression regimens were similar between groups. There was no impact of vitamin K on vascular stiffness (treatment effect –0.23 [95% CI –0.75 to 0.29] × 10^–3 mmHg^–1; p = .377), vascular calcification (treatment effect –141 [95% CI – 320 to 38] units; p = .124), nor any other outcome measure. In this heterogeneous cohort of prevalent KTR, vitamin K supplementation did not reduce vascular stiffness or calcification over 1 year. Improving vascular health in KTR is likely to require a multifaceted approach.
Denosumab Recovers Aortic Arch Calcification During Long-Term Hemodialysis
2021, Kidney International Reports
Aortic arch calcification (AoAC) is related closely to mortality risk in patients undergoing maintenance dialysis. Recent experimentally obtained data suggest that osteoprotegerin/receptor activator for nuclear factor κB ligand signal transmission plays a role in de novo chondrogenic transition of vascular cells leading to calcification that is unrelated to bone metabolism. This study investigated the long-term effects of denosumab, an osteoprotegerin mimic peptide, on AoAC.
This study examined 58 patients with an 8 year vintage of dialysis at 1 center for observational study during 2009 to 2020. Denosumab was administered to 28 patients every 6 months. Blood chemical data were used. AoAC proportions were measured using a simple but computed tomography–equivalent computer-based chest X-ray analysis (calcified pieces of areas around the aorta).
Blood chemical data of the control and denosumab groups that did not differ at the start showed differences of mineral metabolism after 30 months of observation. Remarkably, the AoAC proportion increased from 29.4% to 46.25% in the control group but decreased significantly from 25.0% to 20.0% (P < 0.01) in the denosumab group. Denosumab effects on decalcification were not observed 12 months after initiation.
We conclude that long-term use of denosumab is effective to reverse or treat AoAC in patients undergoing hemodialysis.
Vascular Calcification Slows But Does Not Regress After Kidney Transplantation
2020, Kidney International Reports
Medial arterial calcification is a common and progressive lesion in end-stage renal disease that is associated with poor cardiovascular outcomes. Whether this lesion can be arrested or reversed is unknown, and was examined retrospectively by measuring progression of breast arterial calcification before and after kidney transplantation.
Arterial calcification was measured on serial mammograms from patients with previous kidney transplantation and compared to measurements performed before transplantation or in patients on the active waitlist. Serum creatinine >2.0 mg/dl after transplantation or warfarin use were exclusions.
Median (interquartile range) progression of arterial calcification was 12.9 mm/breast per year (5.9 to 32.6) in 34 patients before or awaiting transplantation compared to just 1.2 mm/breast per year (−0.54 to 5.1) in 34 patients after transplantation (P < 0.001). Slowing of progression was also seen in longitudinal analyses of patients with mammograms performed both before and after transplantation. Duration of end-stage renal disease before transplantation but not age, diabetes, baseline calcification, or serum chemistries correlated with progression after transplantation. Significant regression was not observed in any patient.
In this first quantitative study of the effect of kidney transplantation, medial arterial calcification appeared to slow to rates seen in patients with normal renal function, indicating that the effect of renal failure may be completely abrogated. Overall, however, there was no significant regression, suggesting that calcification is irreversible and emphasizing the importance of prevention. Duration of pretransplant end-stage renal disease but not baseline calcification was a determinant of progression, consistent with cumulative, permanent changes to arteries that promote calcification.
The bone-vessel axis in chronic kidney disease: An update on biochemical players and its future role in laboratory medicine
2020, Clinica Chimica Acta
Vascular wall calcification (VC) is highly prevalent in patients with chronic kidney disease (CKD). In CKD, VC is more frequent and severe than in the general population and it is associated with increased cardiovascular mortality and morbidity.
In the last years, laboratory and clinical evidence have drawn the attention to the relationship between bone disease and VC in CKD patients, leading to the concept of a bone-vessel or bone-vascular axis. It means that disorders of bone volume and bone turnover may influence the risk of VC and ultimately the high risk of cardiovascular mortality. In fact, a higher burden of VC has been associated to low bone volume and low bone turnover in hemodialysis (HD) patients with renal osteodystrophy characterized by histomorphometric evaluation of bone biopsies. The molecular mechanisms underlying the regulation of bone cells and vascular cells in CKD are poorly understood.
In this review, we discuss relevant evidence linking bone disorders and VC in CKD and also rising molecular players involved in this bone-vascular axis. Indeed, accumulating data is available for two proposed systems: receptor activator for nuclear factor kB (RANK)/ RANK ligand (RANKL)/osteoprotegerin (OPG) system and inhibitors of Wnt signaling - mainly sclerostin. Although they are promising biochemical markers linking bone formation and bone reabsorption with VC, there is a long way to go as long evidence from laboratory studies is often divergent to the clinical data as will be discussed.
Future prospective studies are needed in order to evaluate the role of these biochemical players as useful clinical markers for VC, bone volume and perhaps bone turnover.

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: Originally published online September 26, 2011.

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Original InvestigationTransplantationProgression of Coronary Artery Calcification and Thoracic Aorta Calcification in Kidney Transplant Recipients

Background

Study Design

Setting & Participants

Predictors

Outcomes & Measurements

Results

Limitations

Conclusion

Section snippets

Patients

Study Cohort

Discussion

Acknowledgements

Atherosclerosis

Am J Transplant

Am J Kidney Dis

Kidney Int

J Am Coll Cardiol

Am Heart J

Am J Cardiol

Kidney Int

Kidney Int

Am J Clin Nutr

Atherosclerosis

Biochem Biophys Res Commun

J Am Col Cardiol

J Am Coll Cardiol

Acute myocardial infarction and kidney transplantation

J Am Soc Nephrol

Cardiovascular complications after renal transplantation and their prevention

Transplantation

Morphology of coronary atherosclerotic lesions in patients with end-stage renal failure

Nephrol Dial Transplant

Arteriosclerosis, vascular calcifications and cardiovascular disease in uremia

Curr Opin Nephrol Hypertens

Mechanisms of vascular calcification in chronic kidney disease

J Am Soc Nephrol

Media calcification and intima calcification are distinct entities in CKD

Clin J Am Soc Nephrol

Arterial calcifications, arterial stiffness and cardiovascular risk in end-stage renal disease

Hypertension

Advanced coronary and carotid arteriopathy in young adults with childhood-onset chronic renal failure

Circulation

Cardiac valve calcification as an important predictor for all-cause mortality and cardiovascular mortality in long-term peritoneal dialysis patients

J Am Soc Nephrol

Coronary artery calcification: a strong predictor of cardiovascular events in renal transplant recipients

Nephrol Dial Transplant

Aortic calcification predicts cardiovascular events and all-cause mortality in renal transplantation

Nephrol Dial Transplant

Progression of coronary artery calcification in renal transplantation and the role of secondary hyperparathyroidism and inflammation

Clin J Am Soc Nephrol

Natural history of vascular calcification in dialysis and transplant patients

Nephrol Dial Transplant

Prevalence and determinants of coronary and aortic calcifications assessed by chest CT in renal transplant recipients

Am J Nephrol

Original Investigation
Transplantation
Progression of Coronary Artery Calcification and Thoracic Aorta Calcification in Kidney Transplant Recipients