The humanistic burden of focal segmental glomerulosclerosis on patients and care-partners in the United States

Focal segmental glomerulosclerosis (FSGS) is a kidney disease characterized by scarring of the glomerulus, vessels which filter waste and excess fluids from the blood, and can ultimately lead to decline in kidney function and progression to kidney failure [1]. FSGS is one of the most common causes of primary glomerulopathy in adults in the United States (US), with an estimated prevalence of approximately 21.2 per 100,000 in the overall US population [2]. Disease onset can occur at any age and occurs in up to 10% of children and 30% of adults with nephrotic syndrome [3]. Although the incidence and prevalence of FSGS vary widely across populations, its incidence has been rising over the past three decades among both children and adults. [1, 4]

Among the heterogenous disorders comprising FSGS, primary FSGS is a rare, idiopathic presentation of the disease [1]. Initial treatment for primary FSGS typically consists of anti-inflammatory drugs (i.e., glucocorticoids), shifting to calcineurin inhibitors if proteinuria does not decline or the patient is steroid resistant [1]. However, despite treatment, an estimated 30–50% of patients with primary FSGS progress to kidney failure within 10 years, [5] with a median time of 12 years across age groups [6]. People of African ancestry are disproportionately affected by primary FSGS [4], and Black individuals in the US experience a fourfold greater risk of FSGS-related kidney failure than White individuals (6.8 vs.1.9 per million) [7]. Reduction in kidney function is accompanied by poorer health outcomes including negative impacts to overall survival. [8, 9]

In addition to the clinical impact of FSGS, the disease is also associated with a substantial economic burden. Patients with FSGS were reported to have significantly higher healthcare costs than matched patients without FSGS, estimated at $59,753 vs. $8,431 per patient per year, respectively, in a retrospective US claims study [10]. The higher costs are largely driven by increased healthcare resource utilization (HRU) due to frequent inpatient and outpatient visits, or the need for life-sustaining hemodialysis or kidney transplant upon progressing to kidney failure [1, 10, 11]. For example, a 2023 retrospective cohort study of 25,699 patients with FSGS-attributed kidney failure identified through the US Renal Data System registry (2008 to 2018) reported high reliance on kidney transplantation, contributing to total annual healthcare costs exceeding $68,000 per patient. [11]

In comparison with the current understanding of the clinical and economic burden of FSGS, the understanding of the associated humanistic burden remains less defined. Kidney failure is associated with substantial physical limitations, fatigue, and other symptoms which profoundly affect patients’ lives [12, 13]. Further, health-related quality of life (HRQoL) is reported to be reduced for patients with any stage of chronic kidney disease [14] across age groups and treatment modalities [15‐17]. However, few studies have assessed the humanistic burden among patients with primary FSGS, and none have focused on the burden among their caregivers (care-partners), which is crucial for understanding and meeting the needs of this patient population and providing optimal support for care-partners.

To quantify the humanistic burden of rare kidney diseases from both patient and caregiver/care-partner perspectives, HONUS (Humanistic Burden of Rare KidNey Diseases: Understanding the impact of FSGS and IgAN on Patients and Caregivers Study; ClinicalTrials.gov Identifier: NCT05200871) was designed as a multi-national, cross-sectional survey in consultation with patients with immunoglobulin A nephropathy (IgAN) or FSGS and clinical community members [18]. HONUS enrolled adults with primary IgAN or FSGS, their care-partners, and adult caregivers of children/adolescents with primary IgAN or FSGS from the US, Spain, United Kingdom, Germany, and France. Survey data collection occurred between January 31, 2022 and May 31, 2023 in the US (and between January 19, 2023 and October 26, 2023 in other countries). The objective of this analysis was to quantify the humanistic burden and impact of primary FSGS in the US from the perspective of adults with the disease, as well as that of care-partners for adults with primary FSGS and caregivers for children/adolescents with primary FSGS.

The demographic characteristics (i.e., age, sex, employment status) and HRQoL outcomes of adults and children/adolescents with FSGS and their care-partners/caregivers collected from the online surveys were descriptively summarized. Total scores, composite scores, and/or domain/scale scores of the standardized survey instruments were calculated based on their published scoring manuals. Continuous variables were summarized as means, medians, and standard deviations (SD); categorical variables were summarized as frequencies and percentages.

Mental health and work productivity outcomes of adults with FSGS were compared to those of an external, kidney disease-free control cohort from the 2023 US National Health and Wellness Survey (NHWS; see Supplemental Methods for further details) [22]. Briefly, NHWS controls were weighted via iterative proportional fitting [23] to align their distributions with those observed in adults with FSGS in HONUS based on key sociodemographic attributes and comorbidities (table s1).

Indirect comparisons of outcomes were performed between the HONUS FSGS cohort and weighted NHWS controls. Scores for depression (PHQ-9), anxiety (GAD-7), and work productivity (WPAI:SHP) were compared between adults with FSGS in HONUS and weighted NHWS external controls using independent t-test with robust variance estimation [24] for mean scores in NHWS or Rao-Scott corrected chi-square tests (see Supplemental Methods). An effect size index, Cohen’s d, was reported, with values of 0.2, 0.5, and ≥ 0.8 indicating small, medium, and large effect sizes, respectively. [25] A p value < 0.05 was considered statistically significant. All analyses were conducted in SAS Enterprise Guide 7.1 (SAS Institute, Cary, NC) or R version 4.2 (R Foundation for Statistical Computing, Vienna, Austria).

To our knowledge, this study is the first to evaluate the humanistic burden associated with FSGS in the US from the perspectives of people with FSGS as well their care-partners/caregivers, and to provide comparisons of their HRQoL to that of external controls using established measures. The present findings indicate that, compared to the general US population [26], adults with FSGS experienced greater impairment to both mental and physical health, while care-partners of adults and caregivers of children/adolescents with FSGS both experienced worse mental health, based on the respective components of the SF-12. Additionally, all domains of HRQoL measured by the PedsQL (via caregiver-proxy) were observed to be worse among children/adolescents with FSGS compared with previously published scores in a general pediatric US population [27], with school functioning particularly affected.

Although physical health was impacted to a greater degree than mental health based on the SF-12 component scores among adults with FSGS, over one-third of this population reported moderate to severe depression (as assessed with the PHQ-9) and over a quarter reported moderate to severe anxiety (as assessed with the GAD-7). Notably, adults with FSGS had significantly higher severity of both depression (PHQ-9) and anxiety (GAD-7) compared with external controls without FSGS, illustrating the negative impact of the disease on specific aspects of mental health.

FSGS negatively impacted work productivity among employed adults with the disease as well as that of employed care-partners/caregivers, as assessed with the WPAI. Importantly, adults with FSGS experienced significantly greater overall work impairment and absenteeism compared with external controls without FSGS, underscoring the challenges of sustaining employment with a chronic disease. Although employed care-partners of adults and caregivers of children/adolescents with FSGS both reported high overall work impairment, it was higher among caregivers of children/adolescents, while caregivers of adults reported more substantial activity impairment. This variance could be related to the greater time commitment required for overall caregiving needs of children/adolescents with a chronic disease like FSGS, coupled with normal child-rearing activities. The vast majority of adults and children/adolescents with FSGS, as well as their care-partners and caregivers, reported feeling fear and uncertainty about the future due to the disease. Strikingly, almost one-third of all groups were affected “quite a bit” or “very much” by fear and uncertainty related to FSGS.

There are few published studies on the humanistic burden of FSGS with which to compare the present findings. A 2023 targeted literature review by Aldhouse et al. of qualitative studies reporting on the experience of adult and pediatric patients diagnosed with FSGS in the US and Canada identified six publications and six written/video patient testimonials from a patient advocacy group [28]. Domains that were identified as salient to patients for a conceptual model of their experience included mental wellbeing, physical functioning and activities of daily life, social functioning, and work/school [28], akin to the domains assessed in this study. Similar to the present findings that facial swelling was a burdensome symptom among adults, swelling/puffiness was found to be one of the most commonly reported symptoms of FSGS by both adult and pediatric patients and was reported to cause emotional discomfort and embarrassment [28]. Patients also often reported experiencing pains, aches, and discomfort, including muscular and bone pain, consistent with the high proportion of both adults and children/adolescents in the current study reporting bone or joint pain and headache, as well as the notable proportion of children/adolescents reporting embarrassment.

A study by Carlozzi et al. used semi-structured interviews (i.e., using open-ended questions rather than specific survey instruments) among children and adults with FSGS to identify the most impactful features of the disease on HRQoL [29]. Their results indicated that FSGS had a profound influence on physical, social, and mental aspects HRQoL regardless of age, impacting patients’ physical abilities as well as life participation. As the aim of Carlozzi et al. was to qualitatively describe the most impactful features of FSGS to inform a new HRQoL tool, their results are not directly comparable to the present results using established measures. However, participants in that study similarly reported on the negative impact of their FSGS symptoms on their mood and sense of self, with 45% of children and 60% of adults reporting feelings of anxiety, similar to the current HONUS cohort.

Considering the sparse literature on the burden of FSGS, studies reporting on the humanistic burden of patients with CKD could also be compared to the current study. Davidson et al. reported that scores on two HRQoL measures (Short Form-6D and Health Utilities Index Mark 3) were substantially lower among patients with stage 4 or 5 CKD (mean: 0.67 and 0.59, respectively) [30] than those of the general population (0.76–0.80 and 0.77–0.82 across groups by age and sex in Fryback et al. [31]). Additionally, a study by Nguygen et al. using data from the National Health and Nutrition Examination Survey (2011–2012) reported that people with CKD were 2.2 times more likely to have fair or poor health status compared to those without the disease [32]. A cohort study by Molsted et al. observed that patients with CKD scored significantly lower than the general population on 5 of 8 different HRQoL measures [33]. Therefore, across studies, patients with CKD experienced lower physical and mental HRQoL compared with the general population [30, 32‐36], similar to the current findings in FSGS patients. With these findings in mind, raising awareness of the impact of kidney disease on multiple facets of life could encourage health care professionals to assess HRQoL when treating patients with FSGS. Additionally, partnerships between healthcare teams and advocacy groups could aid in identifying and mitigating the varied impacts of the disease on both patients and their care-partners/caregivers.

The present study contributes valuable information to the limited existing literature about the humanistic impact of FSGS on patients, as well as completely new insights regarding the disease’s impact on care-partners/caregivers of both adult and pediatric patients. However, this study is subject to several limitations, some of which are inherent to survey studies (e.g., the lack of a control group in all comparisons). First, selection bias may exist as adults with FSGS, their care-partners, and caregivers of children/adolescents with FSGS who voluntarily participated in the survey may differ from those who did not. For example, FSGS is more prevalent among people of African ancestry [37] and among men compared to women [1], although the majorities of the current patient cohorts were White and female. This may be related to the demographics of patient advocacy groups from which the cohorts were recruited [38]. Second, the study relied on self-reported survey responses and therefore could be subject to recall or other biases. Additionally, participants’ self- or proxy-reported FSGS diagnosis and disease history may differ from a clinician’s assessment. Third, the study included a small sample of children/adolescents and reports information collected via caregiver-proxy, therefore results for this group should be interpreted with caution. Finally, participant responses may be confounded by the COVID-19 pandemic given data collection was conducted between 2022 and 2023. This broader circumstance may impact socioeconomic status, accessibility of care, health outcomes, and reported HRQoL.

This cross-sectional survey study conducted among US individuals with primary FSGS and their care-partners/caregivers identified impairments to both mental and physical HRQoL in comparison with the US general population. Adults with FSGS experienced heightened levels of depression and anxiety, as well as negative impacts to work productivity among those employed, compared to external controls without the disease. Further, FSGS also negatively impacted the work productivity of employed care-partners/caregivers, particularly caregivers of children/adolescents with FSGS. All groups reported high rates of fear and uncertainty for the future, including children/adolescents with FSGS. These results underscore the need for effective therapies which alleviate patients’ burdensome FSGS symptoms to reduce the negative impacts to their lives, as well as the importance of support for the care-partners and caregivers.

Some of the study methods and results from participants in HONUS have been presented in abstract/poster form at the 2021 American Society of Nephrology (ASN) Kidney Week in San Diego, CA during November 4–7, 2021; the 2022 ASN Kidney Week in Orlando, FL during November 3–6, 2022; the 2023 European Renal Association (ERA) Congress in Milan, Italy during June 15–18, 2023; and the 2024 European Renal Association (ERA) Congress in Stockholm, Sweden during May 23–26, 2024.