Starting Dialysis Is Dangerous
Patients requiring dialysis are subject to significant functional and structural abnormalities, which may sensitize them to conventional mortality risks, as well as create other issues that are unique to dialytic therapy. These drivers of mortality may relate to end-stage CKD, dialytic therapy, and an individual's susceptibility to both (Figure 1 and Table 1). To date, no attempt has been made to assess the relative effects of all of these risks in a particular patient situation. Research up to this point has focused on thresholds, failing to embrace the reality of biology being essentially a continuum (and therefore lacking biological plausibility). It also has been predicated on there being more risk inherent in having advanced uramia than that being faced associated with renal replacement therapy.
(Enlarge Image)
Figure 1.
Chances of survival at any given starting glomerular filtration rate are a complex dynamic balance between the benefits of relieving advanced uremia and the risks of the attendant therapy. The pivot point for this balance is the individual patient tolerability of both the uremia and the proposed renal replacement therapy. This pivot point itself is somewhat different between patients and even within the same patient over a period of time. The relative weight of the risk of being markedly uremic may well be substantially less than those inherent in dialysis (as it is commonly initiated and performed).
Although such an approach might seem difficult, it is not impossible. Risks from therapies can be quantified, such as with the use of advanced real-time functional assessments (tissue perfusion, systemic hemodynamic responses, cardiac responses to dialysis treatment, and others), which can define the response of a healthy human to a particular level of dialytic stress. It may also be possible to focus on biological factors that are acting as integrators of these susceptibilities. Potential candidates might be humoral (markers of tissue injury, inflammation, malnutrition, and others), whole-body functioning (6-min walk test, sit to stand testing, and others), health-related quality of life (with specific testing of disease-related domains and so on), or body composition (measuring hydration or reduction in lean body mass and so on). As an example, muscle mass can be accurately assessed by measuring muscle cross-sectional area (MCSA) on thigh CT. There are many factors already reported as being associated on a cross-sectional study basis with muscle wasting. These include decreasing glomerular filtration rate, dialysis, age, and diabetes. Muscle atrophy can be assessed by various methods, and previous work has shown good correlation between thigh MCSA and functional performance, serum albumin, age, and inflammatory status in CKD stages 4–5, HD, and PD patients. These changes have previously been attributed to inadequate dietary protein intake, but recent advances in our understanding of this area indicate that other processes are involved. There is a prospectively observed significant loss of muscle CSA in late-stage CKD 4, suggesting that these patients are subject to increased disturbance of the catabolic/anabolic balance, presumably as a result of advancing uremia. This occurs at eGFRs between 10 and 20 ml/min. Dialysis initiation based purely on estimation of renal function from serum creatinine runs the danger of allowing patients to 'loose ground' in terms of overall nutritional status in these late stages, and failing to optimally time dialysis initiation. This raises the possibility that we might be able to utilize this acceleration of muscle wasting as an individualized biomarker of increasing metabolic decompensation, providing a rationale for when the appropriate time to start dialysis in an individual might be.
An alternative approach might be to identify those patients at particular risk of the cardiovascular effects of dialysis. An approach based on the detection of large-vessel coronary artery disease is unlikely to be useful, given the relatively reduced significance of such findings in the dialysis population. Appropriate cardiovascular stress studies, more sensitive measures of reduced ventricular function (such as global longitudinal strain), microcirculatory studies, or more advanced analyses of heart rate variability patterns (providing information on autonomic function) all might hold promise. The consequence, however, would potentially be to defer dialysis initiation in those patients with documented patterns of cardiovascular vulnerability. Application of such a strategy might see our frailest and most vulnerable patients allowed to be exposed to worsening uremia, and worsened overall condition when they did commence treatment. The risk/benefit ratio for these patients (Figure 1) may be such that nondialytic conservative management may be the wisest choice.
Conflation of Risk and Susceptibility: Future Directions of Study
Patients requiring dialysis are subject to significant functional and structural abnormalities, which may sensitize them to conventional mortality risks, as well as create other issues that are unique to dialytic therapy. These drivers of mortality may relate to end-stage CKD, dialytic therapy, and an individual's susceptibility to both (Figure 1 and Table 1). To date, no attempt has been made to assess the relative effects of all of these risks in a particular patient situation. Research up to this point has focused on thresholds, failing to embrace the reality of biology being essentially a continuum (and therefore lacking biological plausibility). It also has been predicated on there being more risk inherent in having advanced uramia than that being faced associated with renal replacement therapy.
(Enlarge Image)
Figure 1.
Chances of survival at any given starting glomerular filtration rate are a complex dynamic balance between the benefits of relieving advanced uremia and the risks of the attendant therapy. The pivot point for this balance is the individual patient tolerability of both the uremia and the proposed renal replacement therapy. This pivot point itself is somewhat different between patients and even within the same patient over a period of time. The relative weight of the risk of being markedly uremic may well be substantially less than those inherent in dialysis (as it is commonly initiated and performed).
Although such an approach might seem difficult, it is not impossible. Risks from therapies can be quantified, such as with the use of advanced real-time functional assessments (tissue perfusion, systemic hemodynamic responses, cardiac responses to dialysis treatment, and others), which can define the response of a healthy human to a particular level of dialytic stress. It may also be possible to focus on biological factors that are acting as integrators of these susceptibilities. Potential candidates might be humoral (markers of tissue injury, inflammation, malnutrition, and others), whole-body functioning (6-min walk test, sit to stand testing, and others), health-related quality of life (with specific testing of disease-related domains and so on), or body composition (measuring hydration or reduction in lean body mass and so on). As an example, muscle mass can be accurately assessed by measuring muscle cross-sectional area (MCSA) on thigh CT. There are many factors already reported as being associated on a cross-sectional study basis with muscle wasting. These include decreasing glomerular filtration rate, dialysis, age, and diabetes. Muscle atrophy can be assessed by various methods, and previous work has shown good correlation between thigh MCSA and functional performance, serum albumin, age, and inflammatory status in CKD stages 4–5, HD, and PD patients. These changes have previously been attributed to inadequate dietary protein intake, but recent advances in our understanding of this area indicate that other processes are involved. There is a prospectively observed significant loss of muscle CSA in late-stage CKD 4, suggesting that these patients are subject to increased disturbance of the catabolic/anabolic balance, presumably as a result of advancing uremia. This occurs at eGFRs between 10 and 20 ml/min. Dialysis initiation based purely on estimation of renal function from serum creatinine runs the danger of allowing patients to 'loose ground' in terms of overall nutritional status in these late stages, and failing to optimally time dialysis initiation. This raises the possibility that we might be able to utilize this acceleration of muscle wasting as an individualized biomarker of increasing metabolic decompensation, providing a rationale for when the appropriate time to start dialysis in an individual might be.
An alternative approach might be to identify those patients at particular risk of the cardiovascular effects of dialysis. An approach based on the detection of large-vessel coronary artery disease is unlikely to be useful, given the relatively reduced significance of such findings in the dialysis population. Appropriate cardiovascular stress studies, more sensitive measures of reduced ventricular function (such as global longitudinal strain), microcirculatory studies, or more advanced analyses of heart rate variability patterns (providing information on autonomic function) all might hold promise. The consequence, however, would potentially be to defer dialysis initiation in those patients with documented patterns of cardiovascular vulnerability. Application of such a strategy might see our frailest and most vulnerable patients allowed to be exposed to worsening uremia, and worsened overall condition when they did commence treatment. The risk/benefit ratio for these patients (Figure 1) may be such that nondialytic conservative management may be the wisest choice.
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