Clinical and Laboratory Parameters Predicting Frailty in End-Stage Kidney Disease Patients on Maintenance Dialysis

Introduction

Frailty is a multidimensional clinical syndrome characterized by declining physiological reserves, resulting in an increased susceptibility to stressors and adverse health events. In patients with kidney failure (KF) on hemodialysis, frailty has emerged as a major clinical and public health issue. With increasing patient longevity and expanding dialysis programs, frailty prevalence has reached concerning levels, ranging from 30% to >70% in various studies.^1,2 This heterogeneity in prevalence can be attributed to disparities in assessment tools, patient demographics, comorbidities, and geographic settings.

Multiple interconnected factors, including chronic systemic inflammation, malnutrition, reduced physical activity, comorbidity burden, and dialysis-specific variables such as dialysis vintage and adequacy, contribute to frailty in this population. Frailty has consistently been associated with heightened mortality, frequent hospitalizations, increased fall risk, and diminished quality of life.^3,4 These repercussions emphasize the need for early detection and appropriate management.

Although recognition of frailty in dialysis populations is rising globally, data from India remain limited, particularly concerning local dialysis practices, patient age at initiation, and dialysis frequency/dose. The present study aims to address this gap by providing a detailed overview of frailty prevalence and its clinical and laboratory predictors in Indian patients on hemodialysis.

Materials and Methods

This study was conducted on patients undergoing maintenance hemodialysis (MHD) at our hospital. Of 200 patients screened for eligibility between June 2022 and December 2023, 170 were assessed for frailty. Patients with (1) age ≥18 years, (2) undergoing the same modality of hemodialysis for at least 3 months, and (3) the ability to provide informed consent, were included. Patients were excluded in case of (1) incomplete frailty assessment, (2) active infection and significant disability, i.e., unable to ambulate, and (3) lack of reliable bystander.

The Institutional Ethical Committee approved this study (2024-159-DM-EXP-600). All participants provided written informed consent by themselves or family members.

We identified a set of factors that we suspected might be associated with frailty. These included demographic factors such as age, sex, BMI, mid-upper-arm circumference (MUAC), socio-economic status, comorbidity, viz., diabetes, hypothyroidism, cerebrovascular accident, coronary artery disease, and prior renal transplant. Dialysis-related factors like dialysis vintage, frequency of hemodialysis, mode of dialysis - hemodialysis vs. hemodiafiltration, intradialytic hypotension, vascular access, and prior history of vascular intervention. Laboratory parameters, viz., the serum levels of hemoglobin, blood urea nitrogen, creatinine, electrolytes, albumin, total cholesterol, triglyceride, calcium, phosphate, alkaline phosphate, intact parathyroid hormone (iPTH), Vitamin D, and iron profile.

Frailty was assessed using the Fried Frailty Phenotype and the Clinical Frailty Scale (CFS). Fried's Frail Phenotype was assessed according to the criteria developed by Fried and colleagues in 2001, which defines frailty based on five specific criteria: weakness, unintentional weight loss, slow gait, exhaustion, and low activity.⁵ The presence of at least 3/5 is considered frailty. The complete definition has been attached in the Supplementary File.

The CFS is a clinical judgment-based tool designed to assess frailty by evaluating specific domains, including comorbidity, function, and cognition. It has 7 categories, from very fit (1) to severely frail (7). Patients with a score of ≥5 were classified as frail according to the CFS scale.⁶ A complete description has attached in the Supplementary File.

Results

As illustrated in Figure 1, 200 patients from the dialysis unit of our hospital were enrolled in the study. However, 30 patients were excluded: five were missing data on one or more frailty components, 10 were <18 years old, and 15 did not complete the frailty assessment due to significant disability. The remaining 170 patients fulfilled the inclusion criteria.

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Figure 1:

Flow diagram illustrating the enrollment and selection process of participants in the study. A total of 200 patients undergoing maintenance hemodialysis were screened between June 2022 and December 2023. Of these, 30 patients were excluded: 5 due to missing data on one or more frailty components, 10 for being <18 years of age, and 15 who did not complete the frailty assessment. Ultimately, 170 patients were included in the final analysis to evaluate the prevalence and risk factors associated with frailty in this population.

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The clinical characteristics of the patients have been shown in Table 1. Participants' mean age was 37.2±11.8 years (Median age 36 years, IQR 18–70 years), 28.2% were females, and the median dialysis vintage was 32 months (IQR 8-251). The mean BMI of the cohort was 21.2 ± 3.98 kg/m². Diabetes was the most common comorbid illness seen in 17% of patients, followed by hypothyroidism (15.8%); 10.5% of patients had a prior history of renal transplant, and 10% had a documented history of coronary artery disease either diagnosed by non-invasive or invasive tests.

Frail patients were older (42.3±11.47 years) than those of non-frail patients (32.2±10.12 years) [p<0.001]. Frailty was more common in females (79.1%) than males (37.7%) [p=<0.001].

Diabetes was present in 25% of frail patients compared to 9.3% in non-frail patients [p=0.007]. Similarly, hypothyroid was present in 29.8% of frail patient and 2.3% of non-frail patients [p=<0.001]. Patients suffering from coronary artery disease in frail and non-frail groups were 16.7% and 3.5%, respectively [p=0.004]. Patients with longer dialysis vintage (p<0.001) and intra-dialytic hypotension (p=0.001) were more likely to be frail. We found that frail patients had lower MUAC (p=0.05), lower albumin levels (p<0.001) and lower total cholesterol levels (p<0.004).

As shown in Table 2, of the patients studied, 82.4% and 17.6% underwent twice-and thrice-weekly MHD, respectively. Conventional hemodialysis and hemo-diafiltration were seen in 88.2% and 11.8%, respectively. AV fistula was the predominant dialysis access used in 95.3% of patients; only 4.3% used tunnelled dialysis catheters. History of prior vascular intervention, either central venoplasty or peripheral fistuloplasty, was seen in 22.3% of patients. A history of hospitalization over the past year was seen in 31.1% of patients. Peripheral vascular disease was seen in 4.7% of the cohort.

According to Fried's classification criteria, 49.4% (84/170) of the cohort were frail. Frailty was found in 37.7% (46/122) of males and 79.1% (38/48) of females. Similarly, frailty was found in 72.4% (21/29) of diabetics and 92.5% (25/27) of patients with hypothyroidism.

Multivariate logistic regression analyzed factors predicting frailty, as shown in Table 3. The risk factors independently associated with frailty included female sex (OR=4.794, 95% CI 1.662–13.831, p=0.004), age > 37 years (OR=5.993, 95% CI 2.004–17.923, p=0.001), MUAC < 22 (OR=4.238, 95% CI 1.557–11.531, p=0.005), albumin < 4 (OR=5.11, 95% CI 2.084–12.548, p<0.001), total cholesterol < 150 (OR=2.758 (1.093–6.955, p=0.032), presence of intradialytic hypotension (OR=4.651, 95% CI 1.133–19.094, p=0.033), and hypothyroidism (OR=6.074, 95% CI 1.031–35.775, p=0.046).

As shown in Table 4, CFS was compared with Frail's phenotype. A 52.38% sensitivity and 94.19% specificity were observed with positive and negative predictive values (PPV and NPV) of 89.9% and 66.94%, respectively.

Discussion

The present study revealed that frailty is common in our dialysis population, more so in females. We also found that frailty is associated with ageing, lower MUAC, lower serum albumin level, hypothyroidism, hypocholesterolemia, and intradialytic hypotension. Coronary artery disease, diabetes, longer dialysis vintage, and TUG were associated with frailty on univariate but not multivariate analysis.

Similar to our findings, Beckwith et al. noted that 47.2% of females on the kidney transplant waitlist were frail or pre-frail, in contrast to 22.5% of men.⁸ Johansen et al. reported that females had twice the odds of frailty compared to men.⁹ Another study from India, which included 374 patients from two hemodialysis units, also showed that females experienced significantly more intradialytic complications, such as hypotension and cramps, compared to males; however, male participants were 72.7% in that study.¹⁰ Female patients likely face greater frailty due to biologically lower muscle mass and functional reserves.^11–13

Ageing is associated with frailty. As found in ICKD study, ESKD patients in India are much younger as compared to the western population.¹⁴ Patients above the median age of 37 years were associated with frailty in our study. The younger age profile of our cohort likely reflects differences in population demographics, earlier onset of ESKD in India due to higher rates of untreated or late-detected chronic kidney disease, and additionally, older adults with multiple comorbidities may be less frequently referred or accepted for long-term dialysis in public sector. According to a nationwide study, most dialysis patients in India fall within 31–60 years; in contrast, dialysis patients in Japan had a mean age of 67.5 years, with 65% of patients being ≥65.¹⁵ This disparity in the demographic characteristics of hemodialysis patients differs markedly between India and western nations and may be potentially influencing frailty, treatment outcomes, and survival rates. Although frailty is generally viewed as a geriatric syndrome, our data support its relevance even among younger ESKD patients. Muscle strength, rather than muscle mass, is a stronger predictor of functional decline and mortality among older adults, emphasizing the role of physical function in assessing frailty.¹⁶

Sarcopenia is highly common among hemodialysis patients and is linked not only to frailty but also to the protein-energy wasting (PEW) syndrome, also known as malnutrition-inflammation complex syndrome (MICS), which carries a poor prognosis.^17,18 Furthermore, we identified an association between frailty and indicators of malnutrition such as serum albumin, total cholesterol, and MUAC. A major reason for frailty could be the poor nutritional status of the patients. A study from Tanzania assessed the nutritional status of 160 hemodialysis patients and found that 61.2% of patients were malnourished, exhibiting significantly lower body mass index, MUAC, waist circumference, serum albumin, and total cholesterol levels.¹⁹ Our previous study on nutritional parameters has also shown that ∼70% of patients are malnourished when starting peritoneal dialysis, and there is a confounding effect of comorbidities and malnutrition in these patients.²⁰

The prevalence of frailty varies widely in dialysis units with varying practices. The variations in the prevalence of frailty among hemodialysis patients can be attributed to several factors, including differences in the characteristics of the study populations, such as age, existing health conditions, as well as disparities in how frailty was identified and assessed. Typically, three categories of tests are utilized to detect frailty: those involving physical assessments to define a frail phenotype, like Fried's criteria;⁵ subjective assessment scales such as the Clinical Frailty Score by Rockwood⁶ in Canada; and multi-dimensional tools that evaluate various aspects of frailty including cognitive function, dependency level, psychological state, social support, and physical condition, such as the Groningen Frailty Indicator,²¹ Tilburg Frailty Indicator,²² and Edmonton Frail Scale.²³ Nevertheless, the Fried Frail Phenotype is the most validated and widely adopted tool. Studies have reported prevalence rates of 21.9–73% when using this assessment method.^16,24,25 Our study found the overall prevalence of frailty to be 49.6%. Our study compared Frail's phenotype with the CFS and found that 49.4% of patients were classified as frail under Frail's phenotype, whereas only 28.8% were frail as per CFS. The difference underscores that the two tools may capture various facets of frailty. However, the Fried Frailty Phenotype and the CFS are used to assess frailty, with varying focus and methodology.²⁶

Similar to our findings, a systematic review highlighted that frailty is prevalent in ∼42% of adult hemodialysis patients. It is associated with longer dialysis vintage and poorer health outcomes, including increased mortality rates.²⁷ The patients with extended dialysis duration exhibit lower physical performance and more significant comorbidity burden, collectively contributing to their frail status.²⁸ Additionally, a longitudinal study emphasizes the need for interventions to improve physical function and nutritional status for patients with longer dialysis vintage to mitigate the risk of frailty.¹⁵

The association of comorbidities like diabetes, hypothyroidism, and coronary artery disease with frailty is expected. Despite many patients progressing to ESKD due to diabetes, only a subset of them continue on dialysis or translate to renal kidney transplantation.^29,30 These patients tend to have an inflammatory milieu that accelerates metabolic aging, combined with underlying chronic kidney disease, characterized by protein-energy wasting, anemia, acidosis, chronic inflammation, oxidative stress, and vascular calcification, with increasing risk of developing frailty.^18,13,31

Our study found diabetes as a risk factor for frailty in univariate analysis; however, diabetes lost its significance after adjusting for other parameters. The comparatively lower diabetes prevalence could be attributed to advanced systemic complications or poor vascular access, may face barriers to enrollment in long-term dialysis programs in public-sector settings. This selection bias, driven by limited resources and a high demand-to-supply ratio, might have contributed to the underrepresentation of diabetic ESKD patients in our study. A meta-analysis by Lee et al. also found that diabetes mellitus significantly increases the risk of frailty (2.4 times) in patients undergoing hemodialysis.²⁷ Another study involving 355 chronic hemodialysis patients revealed that those with diabetic nephropathy had a considerably higher prevalence of frailty (28.0%) than those without (16.5%), highlighting the impact of diabetes-related kidney disease on frailty in dialysis patients.³²

The relationship between IDH and frailty is bidirectional. IDH may be a marker of underlying frailty and a contributing factor to its progression. We also found that intradialytic hypotension, linked to adverse long-term outcomes in dialysis patients, was associated with frailty. Patients experiencing intradialytic hypotension have higher mortality rates and an increased incidence of myocardial stunning during dialysis.^13,31,33

Similar to our findings, a cross-sectional study from Somalia also found a high prevalence (28%) of hypothyroidism in hemodialysis patients, and they also found hypothyroidism was more common in patients with diabetes, hypertension, and heart disease, suggesting that thyroid dysfunction is prevalent in dialysis population and may contribute to frailty.³⁴

The bidirectional relationship between frailty and cardiovascular disease deserves attention. Frail patients are more susceptible to adverse cardiovascular events, and vice versa, due to overlapping risk pathways such as inflammation, oxidative stress, and vascular calcification. Dialysis-related factors, such as more extended dialysis vintage and intra-dialytic hypotension, were strongly associated with frailty. Intradialytic hypotension leads to fatigue and functional decline post-dialysis, which can exacerbate frailty symptoms. A study from Taiwan showed that frail patients had a 1.63-fold higher risk for vascular access complications, though this was not seen in our study.²⁸

Emerging evidence also links frailty with cognitive decline. A cross-sectional study from South India by Gopinathan et al. found that frail elderly hemodialysis patients had significantly higher rates of cognitive dysfunction, reinforcing the idea that frailty is not only a physical but also a neurocognitive syndrome in this population.³⁵

The study highlights the associations of multiple clinical and laboratory parameters with frailty, which can be monitored to assess frailty. We utilized Fried's criteria for frailty, which incorporates more accurate assessments of physical performance compared to criteria solely based on self-reported questionnaires. While this study provides valuable insights, it is not without limitations. This was a single-center cross-sectional study. A larger sample size with longitudinal follow-up will inform us on the impact of hemodialysis on frailty.

Firstly, future research should focus on longitudinal studies to assess how frailty evolves, identify critical periods for intervention, and inform strategies to mitigate its progression in hemodialysis patients. Secondly, there is a need for RCTs to evaluate the effectiveness of targeted interventions aimed at reducing frailty in MHD patients. Thirdly, incorporating frailty assessments into routine clinical practice in dialysis units could improve patient outcomes. Telehealth and mobile health applications can facilitate ongoing monitoring of frailty markers and promote compliance with exercise and nutrition programs. Lastly, a multidisciplinary approach by encouraging collaboration among nephrologists, geriatricians, dietitians, and physical therapists can create a comprehensive care model that addresses our patients' multifaceted nature of frailty.

In conclusion, frailty is a prevalent problem in the dialysis population. It is associated with female gender, ageing, nutritional parameters, intradialytic hypotension, low serum albumin, hypothyroidism, and hypocholesterolemia. Identifying key risk factors may provide a foundation for targeted interventions to prevent and manage frailty in this vulnerable population. Future research should focus on developing and testing specific interventions to reduce frailty.