The Kidney Function Decline Caused By The Development Of Chronic Kidney Disease
Mar 25, 2022
Contact: Audrey Hu Whatsapp/hp: 0086 13880143964 Email: audrey.hu@wecistanche.com
PART Ⅰ Ⅱ: Kidney function and symptom development over time in elderly patients with advanced chronic kidney disease: results of the EQUAL cohort study
Cynthia J. Janmaat , Merel van Diepen and et al.
ABSTRACT
Background: Initiation of renal replacement therapy often results from a combination of kidney function deterioration and symptoms related to chronic kidney disease (CKD) progression. We investigated the association between kidney function decline and symptom development in patients with advanced CKD(chronic kidney disease). Methods. In the European Quality study on treatment in advanced CKD(chronic kidney disease) (EQUAL study), a European prospective cohort study, patients with advanced CKD(chronic kidney disease) aged ≥65 years and a kidney function that dropped<20mL/min/1.73 m²were followed for l year. Linear mixed-effects models were used to assess the association between kidney function decline and symptom development. The sum score for symptom number ranged from 0 to 33 and for overall symptom severity from 0 to 165, using the Dialysis Symptom Index.
Results. At least one kidney function estimate with symptom number or overall symptom severity was available for 1109 and 1019 patients, respectively. The mean (95% confidence interval) annual kidney function decline was 1.70(1.32;2.08)mL/min/1.73 m².The mean overall increase in symptom number and severity was 0.73(0.28;1.19)and 2.93(1.34;4.52)per year, respectively. A cross-sectional association between the level of kidney function and symptoms was lacking. Furthermore, kidney function at cohort entry was not associated with symptom development. However， each mL/min/1.73 m² of annual kidney function decline was associated with an extra annual increase of 0.23(0.07;0.39)in the number of symptoms and 0.87(0.35;1.40) in overall symptom severity.
Conclusions. A faster kidney function decline was associated with a steeper increase in both symptom number and severity. Considering the modest association, our results seem to suggest that repeated thorough assessment of symptom development during outpatient clinic visits, in addition to the monitoring of kidney function decline, is important for clinical decision-making.
Keywords: chronic kidney disease, clinical epidemiology, kidney function, kidney function decline, symptoms
DISCUSSION
In our study of older adults with advanced-stage CKD(chronic kidney disease), we found that a faster kidney function decline was associated with a steeper increase in the symptom burden over time in patients with advanced CKD(chronic kidney disease). For each unit（=mL/min/1.73m²） annual decline of kidney functions the increase in number and severity of symptoms steepens, with 0.23 and 0.87 per year. This may seem modest, but corresponds to～30% of the mean annual increase in both symptom number and severity. We found neither a cross-sectional association in the level of kidney function and symptoms nor an association between baseline kidney function and symptom development during the pre-dialysis phase.
The symptom burden was substantial in our study population, which has been shown previously at baseline [30]. The symptom number at cohort entry is in concordance with observations in the literature, reporting an average number of symptoms between6 and 20 symptoms in patients with CKD(chronic kidney disease) [6,31]. Our symptom severity was somewhat higher than reported by Almutary et al. [25]. Our mean annual increase in the number of symptoms was similar to the increase of approximately half a symptom found in the 24-12 months prior to reaching the end-point dialysis, transplantation or death in the study of de Goeij et al. [9]. We found a mean(95% CI) increase in symptom severity of 2.93(1.34;4.52) per year. Our study is the first that examined the increase in symptom severity over time in CKD(chronic kidney disease) patients. It is important to distinguish between symptom num-ber and symptom severity in each individual patient [4,25]. A higher symptom number does not necessarily mean that these patients experience a higher symptom severity. In a previous EQUAL study, we demonstrated that both symptom number and symptom severity influence the patient-reported health-related quality of life [2]. The contribution of symptoms to the quality of life variable was also larger than any other condition (e.g. age and comorbidity) investigated.
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The pathophysiological mechanisms underlying the onset of these symptoms and the interplay with kidney function are still not fully understood [32]. It is expected that with disease progression, the subjective manifestation of that condition(ie. symptoms) will increase. This assumption also seems applicable to the symptom development in patients with advanced CKD(chronic kidney disease): an increased number of symptoms and increased symptom severity were experienced by patients with a faster kidney function decline. However, this relationship is not as straightforward as it appears. As in previous research that explored the relationship between kidney function and symptoms, we found no cross-sectional association between the level of kidney function and either symptom number or severity [3,9,33,34]. Murphy et al. found no cross-sectional association between eGFR and either symptom number or severity in conservatively managed patients with advanced CKD(chronic kidney disease) [3]. Furthermore, de Goeij et al. showed that symptoms and eGFR-MDRD were not correlated in patients with CKD(chronic kidney disease) Stages 4 and 5 at four different time points during pre-dialysis care [9]. Apparently, the symptom score varies widely in patients with the same kidney function, considering the absence of these associations, and several possible explanations exist for these differences. First, the timing of symptom onset differs between patients, ie. at different levels of kidney function [9,29]. Secondly, the literature suggests that, in addition to disease progression itself, social and psychological determinants play an important role in symptom development [32]. In particular, psychological determinants are deemed to be relevant for patients' experience of symptoms and their perception of symptom burden, for example, illness perceptions and coping strategies [32,35,36]. Thus, the lack of cross-sectional associations could be because patients with the same kidney function could report a variety of symptom num-ber and severity due to differences in psychological factors[33-38]. In addition, CKD(chronic kidney disease) patients often have several comorbid conditions that would also contribute to the overall symptom burden. All of the above would dilute the true effect of symptoms caused by low kidney function in any cross-sectional investigation. Studying the effect of kidney function loss and symptom development over time makes it easier to disentangle the association with kidney function on symptom burden per se.
To our knowledge, this is the first study that examined the longitudinal association between change in kidney function and change in symptoms over time in patients with advanced CKD(chronic kidney disease). In contrast to our findings, Brown et al. found no association between categories(stable, improved or worsening) of symptoms and stable or decline in eGFR in elderly non-dialysis patients with CKD(chronic kidney disease) Stage 5[39]. However, we investigated the continuous change in kidney function and symptoms. The lack of an association in the study of Brown et al. could be explained by the lack of adjustment for confounding and the loss of information by categorizing the change in symptoms. We extended these findings by showing the impact of a faster kidney function decline on the more progressive increase in symptoms over time in patients with advanced CKD(chronic kidney disease), including adjustment for confounding. In addition, further research on this topic is warranted to unravel the mechanisms underlying the interplay between kidney function decline and symptom development, and the possible role of psychological factors (e.g.illness perceptions)in the onset and development of symptoms. It is important that healthcare professionals continue to focus on supporting patients in finding a way to deal with complaints and symptoms [40].
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A major strength is that the EQUAL study is a large European multicentre prospective cohort study of incident patients with advanced CKD(chronic kidney disease) of at least 65 years of age. This allowed us to examine the longitudinal association between kidney function decline and symptom development. The study design, with a combination of limited exclusion criteria and the elimination of survivor bias by following patients from a common starting point (defined as incident eGFR≤20mL/min/1.73 m²）， increases the generalizability of the obtained results to the clinical practice of pre-dialysis care for elderly patients. Limitations include the use of a single eGFR at each time point, possibly not reflecting the variability in eGFR. However, this is common in real-world clinical practice. Furthermore, the current analysis is restricted to the responders with at least one follow-up measurement. However, the baseline characteristics of these responders are similar to the characteristics of excluded patients. Furthermore, comparable results were obtained when confining the analyses to the 13 CKD(chronic kidney disease)-related symptoms or individuals with three available measurements of kidney function and symptoms. We should note that the advanced age of the cohort limits the generalizability to the whole non-dialysis patient population with CKD(chronic kidney disease) Stages 4 and 5 and results should only be generalized to patients who are at least 65years old. We should acknowledge the possible limitations of the use of eGFR estimated based on serum creatinine since serum creatinine excretion declines in the elderly and is determined by a person's size and muscle mass. Furthermore, we assigned equal weight to all symptoms to build a sum score based on the methodology of Abdel-Kader et al.[15]. However, some symptoms could be more burdensome than others, although the literature on this is scarce, therefore we were not able to assign different weights to each symptom. Finally, the DSI is the most commonly used symptom questionnaire, although it was developed and validated in dialysis patients. However, the DSI has been used in non-dialysis-dependent patients before[41, 42]. The DSI is used in the EQUAL study because the EQUAL study captures the pre-dialysis, transition and dialysis phases.
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Although healthcare providers are aware of the symptom burden in patients with advanced CKD(chronic kidney disease), and evaluation of symptoms is rated as important in the KDIGO guidelines[8], the evidence behind this recommendation is 'not graded'. This complicates anticipating treatment choices and advising when to initiate dialysis for symptom relief. Our results seem to suggest that repeated thorough assessment of both symptom bur-den and severity, in addition to the monitoring of kidney disease progression, is important throughout the pre-dialysis period, for instance using Patient-Reported Outcomes Measures(PROMs). Current research such as the Symptom monitoring WIth Feedback Trial(SWIFT)in Australia/New Zealand and OPTimising routine collection of electronic Patient-Reported Outcomes into disease registries (OPT-ePRO) in the UK are investigating the effectiveness of routinely capturing PROMs in renal care. The underlying purpose is to improve symptom control, reduce symptom number and severity, and to prepare for end-stage kidney disease care. Developing better treatments to reduce symptoms of CKD(chronic kidney disease) is also suggested as the main research priority by patients [7]. Future research should focus on which CKD(chronic kidney disease)-related symptoms possibly increase the most with kidney function deterioration. Additionally, uraemic signs and symptoms were rated as the most important factor guiding the timing of dialysis initiation in an international survey [43]. The important role of physical symptoms in deciding when to start dialysis was also seen in the IDEAL study [11]. Furthermore, each additional sign or symptom has been shown to be associated with a higher odds for ear-lier dialysis initiation [odds ratio of 1.16(95% CI1.06;1.28)per symptom] in nursing home residents [44]. For future research, it would be interesting to investigate whether the increase in symptom burden is associated with time to dialysis initiation or hospitalization; a longer follow-up would be needed in order to provide enough events. Ultimately, a clinical decision rule, including kidney function decline and symptom development, may be useful to decide what the optimal timing is for dialysis initiation. Of course, we have to keep in mind that non-specific symptoms could be related to other comorbid conditions or illnesses precipitating early dialysis initiation among some providers.
To conclude, we showed that a faster kidney function decline is associated with a more progressive increase in both overall symptom number and severity in patients with advanced CKD(chronic kidney disease). Considering the modest association, our results seem to suggest that repeated thorough assessment of symptom development during outpatient clinic visits, in addition to the monitoring of kidney function decline, is important for clinical decision-making.
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