European Journal of Cardiovascular Medicine

Dyspnea, or breathlessness, is a common and often undertreated symptom in patients with chronic kidney disease (CKD). Dyspnea is frustrating not only for patients but also for their primary healthcare providers. Patients with persistent breathlessness often feel anxious and dissatisfied, leading to frequent clinic visits. Physicians often struggle to pinpoint the exact cause of dyspnea and may hesitate to order extensive investigations unless symptoms become severe. This diagnostic dilemma leads to delayed recognition of serious underlying conditions, such as left ventricular dysfunction (LVD), fluid overload, pulmonary hypertension and various pulmonary causes as direct consequences of CKD. The most common contributor to dyspnea in CKD is fluid overload, which leads to pulmonary congestion and interstitial edema, exacerbating breathlessness, particularly in end-stage renal disease (ESRD)[1]. Left ventricular dysfunction (LVD) is another major determinant, as CKD is associated with increased left ventricular hypertrophy (LVH), diastolic dysfunction with elevated LV filling pressures and LV systolic dysfunction in later stages[2]. These cardiac abnormalities often precede symptomatic heart failure and can serve as key predictors of dyspnea in CKD patients. Additionally, anemia is a common and defining complication of CKD which results in reduced oxygen delivery to tissues, leading to fatigue and dyspnea[3].

Developing countries face an increasing burden of patients with CKD with 13.4% of global prevalence[4]. Previous studies estimate that 30–60% of CKD patients experience some degree of breathlessness during the course of their disease[5] Most of these studies focus on advance-stage CKD patients or those who are on maintenance haemodialysis rather than the broader CKD population. Our study aims to investigate the multifactorial causes and prevalence of dyspnea in CKD and assess predictors of left ventricular dysfunction, providing valuable clinical data for early diagnosis and targeted interventions for its prevention.

The study was conducted at a tertiary care center in a Medical college and Hospital in Maharashtra. This was a prospective observational study in which 120 patients with age more than 18 years were included with either newly diagnosed chronic kidney disease or previously diagnosed CKD patients on regular treatment. All patients were followed regularly for 18 months with follow up assessment at 6 months from enrollment. The diagnosis of CKD was based on the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 criteria[6]. All such patients who were clinically stable for past 30 days and willing to participate in the study were included. Patients with conditions that could confound the assessment of dyspnea were excluded. Established chronic respiratory diseases such as COPD, bronchial asthma, interstitial lung disease, and lung cancer were excluded. For a meaningful evaluation of prevalence patients with preexisting anemia were included but patients with severe anemia (Hb <6 g/dL) were excluded. Similarly, patients with a recent acute myocardial infarction within the past month were excluded, but those with a history of MI who are clinically stable were included. Other exclusion criteria include severe obesity (BMI > 40 kg/m²), any known neuromuscular disease, any acute infections or hospitalization for any cause in the past month.

Baseline characteristics of all enrolled patients were recorded. Demographic and clinical characteristics recorded were age, sex, body mass index (BMI), Comorbidities Hypertension (HTN), Diabetes Mellitus (DM), ischemic heart disease (IHD) and CKD stage. Laboratory parameters such as hemoglobin (Hb), estimated glomerular filtration rate (eGFR), NT-proBNP and serum creatinine were also recorded. Echocardiography was done for all patients and parameters like Left Ventricular ejection fraction (LVEF), Presence of Left ventricular hypertrophy (LVH) by measuring LV wall thickness, Grade of LV Diastolic dysfunction, Pulmonary artery systolic pressures to assess pulmonary hypertension and inferior vena cava (IVC) diameter for volume status assessment. For Pulmonary assessment a chest X-ray to identify signs of pulmonary congestion, interstitial lung disease and pleural effusions, along with pulmonary function tests (PFT), including spirometry was done to assess for obstructive or restrictive lung disease. A high-resolution computed tomography (HRCT) of chest was done only in selected cases when deemed necessary.

Dyspnea was assessed using the Modified Medical Research Council (mMRC) Dyspnea Scale at baseline. Prevalence was determined by the proportion of patients reporting dyspnea symptoms across CKD stages at the time of enrollment. Repeat assessment of dyspnea severity, echocardiographic parameters, pulmonary function (if deemed necessary) and laboratory tests were done at the end of study. Special focus was on the progression of dyspnea, changes in cardiac function during the study period. At the end of the study, patients were categorized into two groups based on dyspnea severity using the mMRC grade: those with no or minimal dyspnea (mMRC grade ≤1) and those with significant dyspnea (mMRC grade ≥2). Comparisons were made between these groups to evaluate differences in clinical and biochemical parameters, including cardiac function, pulmonary function, and laboratory markers. Additionally, patients were grouped based on left ventricular systolic function into a worsened LVEF group, defined as those who experienced a decline in LVEF by ≥10% from baseline, and a maintained or minimally reduced LVEF group, defined as those with an LVEF decline of <10% or no change. Multivariate regression analysis was performed to identify independent predictors of left ventricular dysfunction, assessing associations with study parameters.

STATISTICAL ANALYSIS

Data were analyzed using IBM SPSS software version 26. Continuous variables, such as age, BMI, hemoglobin, NT-proBNP, serum creatinine, and LVEF, were expressed as mean ± standard deviation (SD) or median (interquartile range, IQR) based on the normality of distribution. Categorical variables, including sex, presence of comorbidities (hypertension, diabetes mellitus, ischemic heart disease), presence of LVH and CKD stage, were presented as frequencies and percentages. Comparisons between groups based on dyspnea severity (mMRC grade ≤1 vs. mMRC grade ≥2) and left ventricular function (worsened LVEF vs. maintained/minimally reduced LVEF) were conducted using the Independent t-test or Mann-Whitney U test for continuous variables and the Chi-square test or Fisher’s exact test for categorical variables. Multivariate logistic regression was performed to identify independent predictors of worsened LVEF and significant dyspnea. Variables with a p-value <0.10 in univariate analysis were included in the multivariate model. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were reported, and a p-value <0.05 was considered statistically significant.

There were 4 deaths in the study cohort, and 6 patients were lost to follow-up, hence the final analysis was done with 110 patients. At the time of enrollment, out of 120 patients, 28 (23.3%) had CKD stage 1, 22 (18.3%) had CKD stage 2, 51 (42.5%) had CKD stage 3, 13 (10.8%) had CKD stage 4, and 6 (5.0%) had CKD stage 5. A total of 14 patients were on maintenance haemodialysis (HD) or had undergone HD sessions in past. All deaths occurred in CKD stage 5 patients.

At baseline, the study cohort included 120 patients. The mean age was 58.4 ± 12.6 years, and the mean BMI was 24.7 ± 3.2 kg/m². The mean hemoglobin was 9.8 ± 1.6 g/dL, and the mean estimated glomerular filtration rate (eGFR) was 58.2 ± 21.4 mL/min/1.73 m². The mean serum creatinine was 2.1 ± 1.0 mg/dL, and the mean NT-proBNP level was 1643 ± 1120 pg/mL. The mean left ventricular ejection fraction (LVEF) was 53.6 ± 8.7%. Pulmonary artery systolic pressure (PASP) had a mean value of 32.4 ± 9.1 mmHg.

Table 1: Baseline Characteristics of the Study Population (N = 120)

Out of 120 patients, 74 (61.7%) were male and 46 (38.3%) were female. Hypertension was present in 96 patients (80.0%), and diabetes mellitus in 54 (45.0%). Ischemic heart disease was documented in 24 patients (20.0%). Left ventricular hypertrophy (LVH), as assessed by echocardiography, was present in 63 patients (52.5%). LV diastolic dysfunction was noted in 79 patients (65.8%), with 42 (35.0%) having grade 1, 28 (23.3%) grade 2, and 9 (7.5%) grade 3 dysfunction. Chest X-ray showed pulmonary congestion in 19 (15.8%) and interstitial changes in 9 (7.5%). Pleural effusion was noted in 5 (4.2%) patients. Pulmonary function tests (PFT) revealed an obstructive pattern in 10 patients (8.3%), restrictive pattern in 16 (13.3%), and mixed pattern in 6 (5.0%). High-resolution computed tomography (HRCT) of the chest was performed in 9 patients, and interstitial lung disease (ILD) was confirmed in 4 (3.3%).

Table 2: Echocardiographic and Pulmonary Findings at baseline

At baseline, significant dyspnea (mMRC grade ≥2) was present in 48 patients (40.0%). The prevalence of dyspnea increased with advancing CKD stages, affecting 6 (21.4%) patients in stage 1, 7 (31.8%) in stage 2, 21 (41.2%) in stage 3, 9 (69.2%) in stage 4, and 5 (83.3%) in stage 5. Patients with significant dyspnea had a lower mean hemoglobin level (9.2 ± 1.5 g/dL) compared to those without dyspnea (10.2 ± 1.7 g/dL). Additionally, NT-proBNP levels were notably higher in the dyspneic group (2145 ± 1267 pg/mL) than in the non-dyspneic group (1308 ± 875 pg/mL), reflecting a greater burden of cardiac dysfunction and volume overload.

At the end of the study, 110 patients were available for final analysis after excluding 4 deaths and 6 patients lost to follow-up. Of these, 48 patients (43.6%) had significant dyspnea (mMRC grade ≥2), while 62 patients (56.4%) had no or minimal dyspnea (mMRC grade 0–1). Patients with significant dyspnea had a lower mean hemoglobin (9.2 ± 1.4 g/dL vs. 10.3 ± 1.5 g/dL, p = 0.002) and a higher mean NT-proBNP level (2142 ± 1186 pg/mL vs. 1297 ± 927 pg/mL, p = 0.004) compared to those without significant dyspnea. The mean eGFR was lower in the dyspneic group (52.3 ± 20.5 vs. 62.7 ± 19.8 mL/min/1.73 m², p = 0.01), while the mean serum creatinine was higher (2.4 ± 1.1 vs. 1.9 ± 0.9 mg/dL, p = 0.03).

Table 3: Comparison of Parameters Between Patients with and Without Significant Dyspnea at Study End

A higher proportion of patients with significant dyspnea had LV diastolic dysfunction (79.2% vs. 56.5%, p = 0.009), left ventricular hypertrophy (64.6% vs. 42.0%, p = 0.02), and pulmonary hypertension (PASP ≥ 35 mmHg: 41.7% vs. 22.6%, p = 0.03). The mean LVEF was significantly lower in the dyspneic group (50.8 ± 9.2% vs. 55.7 ± 7.8%, p = 0.01). Pulmonary congestion on chest X-ray was observed more frequently in dyspneic patients (22.9% vs. 10.5%, p = 0.04). Similarly, restrictive and mixed patterns on pulmonary function tests were more prevalent in the dyspneic group (20.8% vs. 8.1% and 8.3% vs. 3.2%, respectively).

Comparison of Patients with Worsened vs. Maintained LVEF

At the end of the study, 28 patients (25.5%) experienced a significant decline in LVEF (≥10% reduction from baseline), while 82 patients (74.5%) had maintained or minimally reduced LVEF. Patients in the worsened LVEF group were older (mean age: 62.1 ± 11.8 vs. 56.8 ± 12.3 years, p = 0.027) and had a higher prevalence of hypertension (92.9% vs. 75.6%, p = 0.034). Diabetes mellitus was more common in the worsened LVEF group (60.7% vs. 40.2%, p = 0.038), as was ischemic heart disease (35.7% vs. 15.9%, p = 0.022)

Figure 1: Predictors of worsening LVEF: Multivariate Analysis

The worsened LVEF group had significantly higher NT-proBNP levels at the end of the study (2201 ± 1284 vs. 1435 ± 1015 pg/mL, p = 0.009) and a higher prevalence of left ventricular hypertrophy (LVH) (71.4% vs. 45.1%, p = 0.015).

Multivariate logistic regression analysis identified higher NT-proBNP (OR: 1.004, 95% CI: 1.002–1.006, p = 0.002), presence of LVH (OR: 2.86, 95% CI: 1.23–6.64, p = 0.014), ischemic heart disease (OR: 3.02, 95% CI: 1.18–7.71, p = 0.021), and diabetes mellitus (OR: 2.25, 95% CI: 1.02–4.94, p = 0.045) as independent predictors of worsening LVEF.

The Kidneys, Heart, and Lungs are linked through various pathophysiological mechanisms. Dysfunction in one organ system often leads to compensatory changes or pathological consequences in the others. This interdependence and co-ordination is a good example of organ cross-talk, where disease in a single organ can initiate or exacerbate dysfunction in others resulting in a complex, multisystem clinical presentation. Dyspnea is a classical symptom of cardiovascular and respiratory disorders, prompting physicians to target these two systems to investigate its cause. However, a range of non-cardiac and non-pulmonary conditions can also present subtly with dyspnea as a key manifestation. Chronic Kidney Disease (CKD), in particular, contributes to fluid overload, anemia, and acid-base imbalances, LV dysfunction; factors that can significantly impact both cardiac and pulmonary function[7,8]. As a result, dyspnea is frequently observed in CKD patients and may be an early or prominent symptom reflecting the multisystem involvement and severity of kidney dysfunction[9].

Dyspnea in CKD patients can result from multiple interrelated mechanisms, including fluid overload causing pulmonary congestion, anemia reducing oxygen delivery, left ventricular dysfunction, pulmonary hypertension, metabolic acidosis leading to compensatory hyperventilation. Additionally, pleural effusions are common, and CKD patients are more prone to lung infections such as pulmonary tuberculosis[10,11]. Recognizing the severity and mechanisms of dyspnea is crucial not only for symptom relief but also for timely intervention, as persistent or worsening dyspnea reflects significant impact of CKD on other organ systems. Moreover, early prediction of progressive dyspnea and left ventricular dysfunction can guide closer monitoring, targeted interventions, and potentially improve clinical outcomes in this vulnerable population[12].

In our study dyspnea was a common and multifactorial symptom in CKD patients, with a 40% overall prevalence, rising significantly with advancing CKD stages (69.2% in stage 4 and 83.3% in stage 5), a finding consistent with previous studies[13]. Contributing factors were anemia, fluid overload, left ventricular dysfunction, pulmonary hypertension, and pulmonary abnormalities including ILD and infections. Notably, restrictive and mixed ventilatory patterns observed in pulmonary function tests, along with evidence of pulmonary congestion or interstitial changes on Chest X-rays. These findings align with previous studies[14]. Unlike many published studies that primarily focused on end-stage or dialysis-dependent patients, our study encompassed a broader CKD population, providing a comprehensive perspective on the multifactorial etiologies of dyspnea across all stages of CKD. A subset of CKD patients is prone to early and severe myocardial involvement with reduced systolic function irrespective of stage of CKD[15,16]. These studies with the help of cardiac MRI, have demonstrated myocardial fibrosis and remodelling. Hence it is important to detect and monitor LV structure and function using Echocardiography which is widely available. In our study, worsening LVEF was observed in 25.5% of patients over 18 months. Independent predictors of reduced LVEF included elevated NT-proBNP levels at baseline, presence of left ventricular hypertrophy (LVH), diabetes mellitus, and ischemic heart disease. LVH, which is a precursor of underlying myocardial fibrosis, can progress to systolic dysfunction over time[17]. These findings emphasize the need for regular cardiac evaluation in CKD patients, even in earlier stages and in those without obvious symptoms.

LIMITATIONS

Our study was conducted at a single tertiary care center, which may limit the generalizability of the findings to broader CKD population in different regions. The relatively small sample size, with 110 patients completing follow-up, may reduce the statistical power to detect more subtle associations. There is a potential for selection bias, as patients with advanced respiratory diseases, recent infections, or other severe comorbidities were excluded, possibly underestimating the true burden of dyspnea and cardiac dysfunction. Since more clinically stable patients were enrolled, those with CKD stage 4 and 5 were underrepresented. While echocardiography was uniformly performed, the absence of advanced imaging such as cardiac MRI may have limited the ability to detect early myocardial changes. Similarly, pulmonary function tests and high-resolution chest CT scans were not performed in all patients, which may have resulted in underdiagnosis of mild or asymptomatic pulmonary involvement. Finally, the follow-up period of 18 months, though sufficient to observe short-term changes in cardiac function, may not fully reflect the long-term changes in left ventricular function.

Persistent dyspnea in CKD patients even if mild, is a significant clinical marker that reflects early and progressive cardiac dysfunction, particularly worsening left ventricular ejection fraction (LVEF). Diabetes, ischemic heart disease, LVH, and elevated NT-proBNP are key predictors for worsening of LVEF. Attention should also be given to pulmonary and hematological disturbances in these patients. Regular cardiac evaluation should begin in the earlier stages of CKD even when symptoms are mild. Routine use of Echocardiography, NT-proBNP, PFTs and HRCT Chest if clinically justified, for evaluation of worsening dyspnea may improve outcomes and reduce repeated clinic visits, and should be integrated into clinical practice.

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