Can We Turn the Symptom Curve?

Symptom science, which focuses on symptom experiences, is becoming increasingly important to develop strategies to prevent or mitigate severe symptoms. Symptom science comprises patient centeredness, symptom clusters, symptom appraisal, and symptom burden, with a goal of identifying strategies and tools for symptom assessment. Many symptoms recognized in symptom science are shared across multiple chronic conditions, such that interventions developed in one medical field can be translated to others (1). Symptom science presents the opportunity to better understand the experience of patients, examine the extent to which symptoms relate to the pathophysiology of chronic disease, and develop targeted therapies.

Patients with CKD experience a wide range of symptoms and severity across CKD stages. Symptom burden increases as the disease progresses, and the related distress is comparable to patients with terminal malignances. Understanding the effect of symptom burden on health-related quality of life may ultimately help to improve clinical outcomes such as survival (2).

In this issue of CJASN, Faye et al. applied a novel strategy to identify subgroups of symptom trajectories among patients with CKD in stages 3–5 within the French CKD–Renal Epidemiology and Information Network (CKD-REIN) cohort (3). The investigators followed 2787 patients to assess symptom burden related to CKD over a period of 5 years. They used the Kidney Disease Quality of Life-36 questionnaire annually to assess symptom dimension, with a total of 9121 measurements. Using a joint latent class-mixed model, Faye et al. identified two distinctive trajectories in symptom burden. In total, 31% of the patients had a trajectory with high severity of symptoms at baseline and worsening over time. The investigators also observed a second trajectory in 69% of the patients with less severe symptoms and a stable trajectory. Significantly, those with high severity and worsening trajectory had a poorer quality of life, higher risk of KRT, and higher risk of death. This study is one of the first to follow symptom burden over time in CKD using a joint latent class-mixed model to identify symptom trajectories and assess the association between symptom trajectories and outcomes.

The descriptive symptoms data for this group of patients with advanced CKD are also informative, with most patients reporting fatigue (83%) and relatively few noting chest pain (24%). The distribution of symptom frequency over the study was relatively stable, with muscle pain, fatigue, itchy and dry skin, and poor appetite demonstrating a higher severity across the 5 years of the study (see Supplemental Figure 2 in [3]). These observations may provide potential therapeutic targets to change the trajectory for patients with advanced CKD.

There are important limitations to the inferences that can be drawn from the analysis of the CKD-REIN cohort. One limitation relates to the homogeneity of the study cohort. The cohort was, on average, 67 years old, and predominantly men (66%) and European, leading to questions of the generalizability of these results to women and non-Europeans. The clinical application may also be limited because these observations do not yield a clinical tool to classify a patient’s trajectory. As the authors note, it is also hard to compare these trajectory models with findings from other CKD cohort studies given the differences in symptom measures, analytic approach, and participant characteristics (4). It is also unknown if the interval of symptom evaluation, from annual to a shorter period, may provide a different picture of those who experienced worsening trajectories. In previous studies, as our group has demonstrated (5,6), symptoms can vary by day, and even across the course of a day. These findings should be replicated with other symptom indices to better understand if these observations are valid for other tools used to measure symptoms in CKD.

Several studies have addressed symptom clusters and their effect in CKD, but more research is still needed to demonstrate whether the treatment of symptoms clusters positively affect patients’ lives. There are multiple factors influencing the biologic mechanism for symptom burden, and these factors are also altered by multiple comorbidities. Furthermore, many of the symptoms are under-recognized or poorly assessed in clinical practice. Many patients experience not only a physical burden, but also negative emotional responses. Yet now, the relationship between symptom burden, quality of life, and negative outcomes has become key to predicting a favorable or unfavorable patient trajectory in kidney disease.

How symptom burden should be managed to achieve a positive effect on patients’ quality of life remains a challenge. Many of the current treatment regimens and medications may have unintended adverse consequences that contribute to reduced well-being and quality of life. It is now more relevant to assess different patients at different stages and target high-risk trajectories early on, with interventions to alleviate distress and poor quality of life, and not just avoid progression to a terminal stage.

It is a priority that we better understand how symptom burden trajectories compared with other symptom science concepts to develop symptom-management strategies that improve quality of life and reduce the risk of death. Several studies have assessed symptom burden using symptom clusters in advanced kidney disease (7,8) but lack a clear solution on how to assess patients with moderate to severe kidney disease in clinical practice, or how to identify those at high risk of worst outcomes. There are burgeoning trials addressing symptom complexes among patients on dialysis, single symptoms such as sleep quality and pain, and the implementation of symptom measures and algorithms to manage symptoms among patients undergoing in-center dialysis. The study by Faye et al. supports the position that treatment of symptoms could possibly improve patient outcomes and highlights the need for these interventions to be extended to patients with CKD stages 3–5.

This important study uses the CKD-REIN cohort to provide two critical observations: first, that over two thirds of patients with CKD have relatively stable symptom severity over 5 years, providing key information to inform clinical decision making. Second, that approximately one third of patients had a trajectory characterized by worsening symptoms, higher risk of CKD progression, worse quality of life, and higher risk of dialysis and death. In addition to disease management, Faye et al. provide further evidence of the need to care for the unpleasant symptoms that cause suffering and affect the well-being of patients with advanced CKD.

Disclosures

M. Unruh reports having consultancy agreements with Cara Therapeutics as chair of a Data Monitoring Committee, noting that this is a consulting agreement between Cara and the University of New Mexico; reports receiving investigator-initiated research funding from Dialysis Clinic Inc.; and reports receiving honoraria from the American Society of Nephrology, National Kidney Foundation, and the Renal Research Institute, related to lectures. The remaining author has nothing to disclose.

Funding

None.

Author Contributions

G. Rodriquez de Sosa and M. Unruh wrote the original draft and reviewed and edited the manuscript.