In this single centre study of a relatively elderly Caucasian population receiving RTT, we have demonstrated that diabetes and vascular disease remain strong predictors of mortality, however contrary to the 5 year data a high calcium-phosphate product no longer correlates with mortality at 10 years. Vascular disease and sepsis account for the majority of causes of death at all stages of dialysis, accounting for 72% of the mortality seen at 5 years reducing to 57% at 10 years with a quarter of all mortality (14/56) represented by cardiac disease.
At 10 years, treatment withdrawal and other causes of death (including respiratory failure, pulmonary oedema and sudden death) collectively have shown the greatest proportional increase over the last 5 years (Table
1). Treatment withdrawal has become a more significant feature and is a common sequelae for those with end stage renal failure (ESRF) on long-term RRT. In some cohorts, treatment withdrawal has been described as an increasingly common cause of death and is related to an aging population with increased co-morbidities, such as diabetes, or occurs in young individuals with severe disease
[16, 17]. Indeed the poor projected survival, reduced added benefit of therapy and increased cognitive impairment seen in ESRF coupled with changing views of clinicians has increased dialysis withdrawal rates. Although we have investigated all-cause mortality as our primary outcome, it is important to note that other end-points for palliative care such as quality of life, ability to make advanced directives and symptom management are more clinically relevant.
The 5 year cumulative survival of patients with diabetes and non-diabetics was 47% vs. 67% (p = 0.03) and then at 10 years was of 22% vs. 31% respectively (Figure
1B; p = 0.03). At 5 years the paths of the two groups were divergent, however the 10 year graph is following a divergent-convergent path showing that therapy may be delaying the natural progression of the underlying disease or that those with diabetes may be experiencing early mortality.
The prevalence of diabetes mellitus in chronic kidney disease (CKD) continues to increase and remains a strong independent cardiovascular risk factor for patients in the general population as well as on dialysis
. Hyperglycaemia, in combination to traditional risk factors not only potentates endothelial damage and inflammation but in addition to diabetic mediators such as reactive oxygen species and cytokines, affects gene structure and function, generating targets for novel epigenetic therapeutics
. In addition to the recognised atherosclerotic processes responsible for these cardiac events, a decreased cardiac velocity reserve has also been observed in diabetic patients with CKD
. The importance of atherosclerosis in this cohort has been well documented and the presence of microalbuminuria has been recognised as a surrogate marker of endothelial injury and hence vascular damage seen in diabetic patients
Intensive intervention of diabetes within a multidisciplinary team, in comparison to a conventional therapeutic approach, has been shown not only to reduce mortality from cardiovascular disease but also reduce the micro and macro-vascular complications of diabetes such as neuropathy, nephropathy and retinopathy
Debate remains about the optimal level of glycaemic control for patients with diabetes on RRT
. Poor glycaemic control has been associated with increased cardiovascular deaths seen after transplantation
. In our study 67% of those transplanted suffered cardiac deaths (30% of whom were diabetic). Aggressive glycaemic control has been shown to be detrimental generating a U-shaped curve for HbA1c. When a patient’s HbA1c is persistently lowered below 6% this is associated with adverse outcomes, demonstrated not only in the general population, but in those receiving dialysis as publicised in the Action to Control Cardiovascular Risk in type 2 Diabetes Mellitus trial
[26, 27]. Although initially aimed at reducing microvascular complications, the increasing cardiovascular mortality that was seen meant the ACCORD trial had to be terminated prematurely. Although near-normal glycaemia has not been shown to reduce cardiovascular events in the short-term
, indeed the majority of our cardiovascular disease mortality was seen within the first 5 years; follow up of long-term randomised control studies is needed to determine optimal glycaemic control. Indeed HbA1c at low levels do not necessarily only reflect diabetic treatment but can also be a reflection of malnourishment. Changes in body composition (e.g. muscle loss) may be associated with outcomes but was not examined.
Our data is in agreement to the data presented in previous studies demonstrating that patients receiving RRT with atherosclerotic vascular disease have higher mortality rates
[29, 30]. Also the number of risk factors for cardiovascular disease increases with the stage of CKD
. Given that the pre-dialysis diagnosis of cardiovascular disease predicted both early and late mortality, we speculate that the reemphasis of both prompt recognition and management of cardiovascular risk factors during the early stages of CKD maybe key to improving survival.
The importance of tight blood pressure regulation has been shown to significantly reduce mortality and morbidity
. However studies have raised concerns about over aggressive blood pressure reduction as blood pressure in relation to mortality, in a situation analogous to diabetes, also follows a U-shaped curve
[33, 34]. Statins have been used successfully in the general population to reduce cardiovascular events by around 34%. In CKD and dialysis patients the data is more complex. Initial studies have shown reduced LDL levels in dialysis patients with no cardiovascular benefit
, while the more recent SHARP study has shown a 17% reduction in cardiovascular events in the overall cohort
. Sub-group analysis however suggests once again no benefit in dialysis patients
. Our analysis did not include blood pressure but instead used cardiac end organ markers of hypertension to indicate the presence of cardiac hypertrophy (ECG changes or cardiac echo). Direct relationship between levels of ambulatory blood pressure and cardiovascular events has not been clearly established by controlled studies in dialysis patients and there is a lack of a significant correlation between blood pressure and cardiovascular events in dialysis patients and no predictive value for mortality. It is also well recognised that blood pressure is subject to error in measurement and consistency and lack of standardization of various factors: the auscultatory method of blood pressure measurement eg Korotkoff sounds; patient position during blood pressure assessment; appropriate cuff size to ensure the cuff bladder encircles at least 80% of the arm is not always performed
Traditional risk factors have been the mainstay of cardiovascular disease primary prevention identified in the Framingham Heart Study. However there is debate whether the same relative risks apply to a dialysis population in the secondary prevention of cardiovascular disease. The presence of “renal-specific” non-traditional risk factors including endothelial dysfunction, inflammation, oxidative stress, insulin resistance, anaemia and changes in vitamin D metabolism may play an even more important role in cardiovascular disease progression in CKD
. Therefore in considering the overall cardiovascular risk factors, a risk score specific to this population whilst incorporating a wide range of factors, including those prior to dialysis (such as renal function at the start of dialysis and microalbuminuria), may aid the stratification of high risk patients
Application of the Tangri risk calculator was predictive of commencing RRT but not mortality while slope change in eGFR was more predictive of mortality suggesting rapid progressors to RRT are more likely to die. This would be in keeping with CKD stage in relation to cardiovascular risk
 and potentially a future non-traditional risk factor to modify cardiovascular risk.
Although, in the previous analysis an elevated calcium phosphate product had a significant effect on early mortality and at 5years, validating previous findings in patients with ESRF
, this was no longer the case after 10 years of follow up (Figure
1C; p = 0.7), reflecting other studies with a similar case mix and follow up
. One hypothesis is perhaps that calcium phosphate is an independent risk factor, or proxy, for those already with significant vascular disease. Those with higher proportions of vascular disease coupled with calcium and phosphate’s reflecting potential statistical predictors of cardiac calcification and mortality may have already perished at 1 and 5 years
. Indeed more aggressive management of vascular risk factors may account for the reduced mortality seen at 10 years. This is, however, speculation of an independent risk factor recorded on first dialysis and would require serial calcium phosphate measurements within a randomised control trial to validate this hypothesis.
There is emerging interest between vitamin D, FGF-23 and Klotho and their relation to cardiovascular risk in patients receiving RRT. An understanding how these factors modulate signalling pathways of mineral metabolism may be influential in modifying patients’ overall vascular risk
[47, 48]. A reduction in Klotho and elevation in FGF-23 culminate in reduced vitamin D levels and increased phosphate with subsequent increased risk of vascular calcification
. From our study perspective, levels of these signalling messengers may have changed with RRT or been influenced by the inherent genetic variations seen in different patient sub-groups altering expression of these factors and conferring protection - a concept proposed by those undertaking molecular biological assays with Klotho