9.1 Summary
Efforts to reduce cardiovascular risk in paediatric CKD have had minimal success over the past few decades. Identifying high-risk patients is difficult as conventional methods of cardiovascular assessment have limitations.
Cardiovascular magnetic resonance imaging has numerous advantages and may be a more valuable tool for clinical assessment in this population. In this thesis, I investigated the utility of CMR for the cardiovascular phenotyping of pre-dialysis CKD in children. In addition, I also conducted two smaller exploratory studies on dialysis and renovascular hypertension children.
Using CMR, I was able to elicit clinically important findings in children with renal disease. Importantly, it did not require the use of MRI contrast, which is both unpleasant for children and contraindicated in CKD. The combination of sensitivity of novel CMR techniques like tissue phase mapping with precision of conventional sequences has made it an effective tool for the detection of subtle abnormalities. The other key advantage of the sequences used is the speed of acquisition. This enabled comprehensive cardiovascular assessment to be performed swiftly. All of this together helped improve the overall patient experience and made it a much more tolerable investigation for children.
9.2 Myocardial abnormalities in paediatric renal disease
A key aspect of this study was the novel detection of sub-clinical systolic and diastolic impairment with CMR. The ability to measure radial and longitudinal function allowed a detailed assessment of uraemic cardiomyopathy. Future studies should investigate how impairment in myocardial mechanics may evolve with disease progression. Larger studies are also needed to confirm the findings of this small exploratory study on dialysis patients. Examining how these parameters may change in dialysis may be helpful for a better understanding of the acute effect of haemodialysis on myocardial mechanics.
This may help to improve current management of dialysis related complications such as myocardial ischaemic insults secondary to intra-dialytic hypotension.
Abnormalities in radial and longitudinal myocardial velocity are likely to be an early manifestation of myocardial involvement, as they appear to precede the development of LVH. Thus, myocardial velocity measured with tissue phase mapping may have a role as a potential imaging biomarker in the future. At present, there are no established normative values for myocardial velocity in children. This will need to be established. In the future, large prospective studies with long-term follow up are required to determine the prognostic significance of these indices and its ability to predict cardiovascular risk.
9.3 Role of systemic vascular resistance in hypertension in CKD
Although the mechanism for hypertension in CKD is multi-factorial, arterial stiffness is widely believed to be the key component in paediatric CKD.
Previous studies have found evidence of increased arterial stiffness, which is consistent with the calcium and phosphate dysregulation and vascular remodelling so frequently seen in this population. Nonetheless, the role of arterial stiffness in the pathogenesis of hypertension is uncertain, even though it may be present. In this thesis, I have shown that it is possible to assess the key components of hypertension simultaneously using CMR in order to determine their relative importance.
Systemic vascular resistance appears to be the most important determinant of hypertension in renal disease in children. This suggests that treatment resistant hypertension in paediatric CKD or renovascular hypertension may be due to a significantly elevated SVR. Further investigation is needed to confirm this. If so, hypertension treatment in this population may be further optimised by therapies that reduce SVR, such as systemic vasodilators. Furthermore, SVR, measured by CMR, may also serve as a potential target to guide management of patients, particularly in resistant hypertension.
Although the dialysis study was exploratory in nature and the numbers were small, the markedly elevated SVR and its association with diastolic dysfunction in peritoneal dialysis were particularly interesting. My findings suggest that the daytime dwell volume may be an important factor, but preload may also be a confounding factor. Larger studies are needed to better understand how preload can affect SVR and if this may have any significant long-term consequences on the myocardium. If so, more work needs to be done to look at how this can be mitigated (such as studying if changing dwell volumes may reduce SVR).
The investigations in this thesis were limited to a cross-sectional evaluation of the determinants of hypertension at a single time point. However, these haemodynamic factors may change as the disease progresses, not least due to fluid accumulation in end stage disease. Understanding how this may evolve will allow clinicians to better tailor treatment to patients at different disease stages.
There are many different causes of elevated SVR in CKD. The relative significance of these mechanisms is uncertain. Future studies may combine CMR haemodynamic measures with other biomarkers (e.g. neurohumoral) to better understand the pathogenesis of raised SVR in CKD and renovascular hypertension. This may be useful for designing future therapies to effectively target key pathological mechanisms at a biochemical level.
The effect of aortic compliance on blood pressure does not appear to be important in paediatric renal disease. Nonetheless, the influence of arterial stiffness on afterload cannot be discounted. In fact, characteristic impedance is one of the key elements determining blood pressure (the other two being SVR and arterial compliance in the 3-element Windkessel model (85)). There is increasing recognition that arterial impedance, i.e. resistance to oscillatory flow, is an important factor in hypertension (159). Thus, methods for impedance analysis such as pulse wave velocity measurement will continue to be an important part of cardiovascular assessment. New CMR protocols have been developed that allow PWV measurements and have been used to demonstrate abnormal vascular function following coarctation of aorta repair (160). Future studies may incorporate this protocol to provide an even more comprehensive evaluation of vascular function in paediatric CKD.
9.4 Conclusion
In conclusion, CMR is a useful tool for the cardiovascular assessment of children with renal disease. The unique findings of vascular dysfunction and sub-clinical myocardial impairment in paediatric renal disease using CMR have clinically significant implications. Future studies are needed to determine the prognostic significance of these abnormalities and to evaluate its utility as potential imaging biomarkers.