Cardiac Magnetic Resonance Imaging Findings in Patients With Chronic Kidney Disease and End-Stage Kidney Disease: A Systematic Review and Meta-Analysis

In this systematic review and meta-analysis, we explored the utilization of cardiac magnetic resonance imaging (CMR) to detect fibrotic changes secondary to uremic cardiomyopathy during the early stages of chronic kidney disease (CKD) and in patients with end-stage kidney disease (ESKD). Uremic myocardial fibrosis can lead to arrhythmia and heart failure, and it is important to detect these changes. CMR offers a noninvasive way to characterize the severity of cardiac remodeling. A comprehensive search of multiple electronic databases was conducted. Studies were divided according to scanner field strength (1.5 or 3 Tesla). The random effects model was used to calculate the pooled mean, 95% confidence interval (CI), standard error, and standardized mean difference (SMD). The I2 statistic was used to assess the heterogeneity between study-specific estimates. The search retrieved 779 studies. From these, 20 studies met the inclusion criteria and had 642 CKD patients (mean age of 56.8 years; 65.2% males; mean estimated glomerular filtration rate (eGFR) of 33 mL/min/1.73 m2) and 658 ESKD patients on dialysis (mean age of 55.6 years; 63.3% males; mean dialysis duration of 3.47 years). CKD patients had an increased left ventricular mass index (LVMi) compared to controls, with an SMD of 0.37 (95% CI: 0.20-0.54; I2 0%; p-value <0.05). ESKD patients also had increased LVMi compared to controls, SMD 0.88 (95% CI: 0.35-1.41; I2 79.1%; p-value 0.001). Myocardial fibrosis assessment using T1 mapping showed elevated values; the SMD of native septal T1 values between CKD and controls was 1.099 (95% CI: 0.73-1.46; I2 33.6%; p-value <0.05), and the SMD of native septal T1 values between ESKD patients and controls was 1.12 (95% CI: 0.85-1.38; I2 33.69%; p-value <0.05). In conclusion, patients with CKD and ESKD with preserved left ventricular ejection fraction (LVEF) have higher LVMi and T1 values, indicating increased mass and fibrosis. T1 mapping can be used for the early detection of cardiomyopathy and as a risk stratification tool. Large, randomized trials are needed to confirm these findings and determine the effect of long-term dialysis on cardiac fibrosis.


Introduction And Background
Cardiac disease is a significant cause of mortality in almost 50% of patients with chronic kidney disease (CKD) and end-stage kidney disease (ESKD).Cardiovascular disease risk occurs independently of comorbidities such as hypertension and diabetes [1].The term uremic cardiomyopathy is commonly used to describe changes to the cardiac structure that occur in kidney disease, and it involves two distinct processes: left ventricular hypertrophy and myocardial fibrosis.Several factors related to preload, afterload, uremic toxins, interleukin 1 alpha (IL-1α), interleukin 6 (IL-6), carnitine deficiency, parathyroid hormone imbalance, high FGF-23, reduced serum Klotho, high circulating phosphate, volume overload, anemia, increased hepcidin, erythropoietin resistance, and endothelial dysfunction bring about these unfavorable nonatherosclerotic changes to the cardiac myocardium.Uremic cardiomyopathy can further lead to arrhythmogenic complications that result in a high prevalence of sudden cardiac death, which is responsible for almost 40% of the deaths in the ESKD population [2].Moreover, interstitial fibrotic changes have been detected in the early stages of CKD prior to the development of left ventricular hypertrophy, indicating that these processes start in early CKD.Cardiac magnetic resonance imaging (CMR) is universally considered the gold standard in assessing left ventricular dimensions due to its high spatial resolution, less interobserver variability, and better border definitions [3].In addition, interstitial fibrosis and edema can be detected by CMR using T1 and T2 mapping [4,5].We aimed to conduct a systematic review and meta-analysis to provide qualitative and quantitative CMR information about changes in uremic cardiomyopathy.
This article was previously presented as a meeting abstract at the 2023 American Society of Nephrology Annual Scientific Meeting on November 2, 2023.

Data Sources and Search Strategy
The following four electronic databases were searched on 3/8/2023 and 3/13/2023 from the inception of each database via a librarian-assisted database search: Medline (PubMed), Embase, Cochrane Central Register of Controlled Trials, and Web of Science (including the Science Citation Index Expanded, Social Science Citation Index, and Arts and Humanities Citation Index).Google Scholar was searched on 3/13/23 using Publish or Perish software, and the first 100 results were selected.We used keywords and controlled vocabulary related to CMR and CKD.A total of 1,295 citations were retrieved.The librarian manually removed duplicates using EndNote's duplicate identification feature [6], leaving 774 results (Table 1).

Study Selection
Two reviewers (D. C. and R. R.) independently reviewed (blinded) abstracts and articles with full texts.The decision to include a study was based on the inclusion and exclusion criteria.The reasons for exclusion were recorded, and disagreements were resolved by further discussion and consulting a third author (R. K.).A web-based collaboration software platform (Covidence, Melbourne, Australia) was used for literature screening [7].The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were used to select the final articles [8].The study protocol was registered in PROSPERO, an international database of systematic reviews, with registration number CRD42023400693.

Data Extraction
A standardized spreadsheet was used to extract demographic, clinical, and radiological data.All the authors performed data extraction, and the extracted data were verified by two authors (D. C. and R. R.).

Statistical Analysis
Continuous variables were expressed as the mean ± standard deviation, and categorical variables were expressed as percentages.Pooled mean estimates and corresponding 95% CIs for continuous variables were calculated using the inverse variance random-effects DerSimonian-Laird method [9].The standardized mean difference (SMD) was calculated when comparing two groups using the random effects model.SMDs of 0.2, 0.5, and 0.8 are considered small, medium, and large, respectively [10].A proportional meta-analysis was performed for dichotomous variables using the random effects model.

Quality Assessment and Risk of Bias
The modified Newcastle-Ottawa scale was used to assess bias since only prospective, retrospective studies and single cohorts of RCTs were included in our study.Studies were scored on study selection (representativeness of the exposed cohort, ascertainment of exposure, ascertainment of outcomes at the start), and outcome (assessment of outcome, follow-up time, adequacy of follow-up) [12].Two authors (D. C. and R. R.) performed the scoring independently.Studies were evaluated for a maximum of 6 points, with a score of 5 suggesting high quality and a score of <5 suggesting low quality.

Search Strategy Results
A total of 779 relevant citations were identified.Following the screening, 156 articles were selected for fulltext review.Of these, articles not meeting the inclusion criteria (n=135) and studies with the same cohort (n=6) were excluded.Studies were separated according to the magnetic scanner strength (1.5 or 3 T).We excluded three studies because they utilized both scanner strengths to evaluate their cohort.Finally, 20 studies were selected for the systematic review and meta-analysis.The literature search strategy is presented in Figure 1.

Quality Assessment
The results of the quality assessment of the 20 studies are described in Table 4.All of the studies scored above five and were considered to be of high quality.
A meta-analysis of three studies with 161 patients showed that the mean LVMi of CKD patients at 1.  Five studies with 181 ESKD patients were analyzed, and their mean LVMi at 1.  McQuarrie et al. looked at LVMi and proteinuria in people with diabetic nephropathy and IgA nephropathy.They found that proteinuria was linked to a higher left ventricular mass in people with CKD stages 2-4.The mean LVMi in their study was 84.8 g/m2, the mean protein-creatinine ratio was 82.5 (23-236) mg/mmol, and the mean LVEF was 69.9%.LVMi was higher in males and lower in patients on renin angiotensin aldosterone system inhibitors [28].Rutherford et al. showed that patients on hemodialysis had increased LVMi, a lower peak global longitudinal strain, and increased global native T1 when compared to healthy controls [24].

Late Gadolinium Enhancement
There were four studies with CKD stages between 2 and 4 reporting LGE after gadobutrol contrast (a nonionic group II agent), and analysis was performed on 112 patients from two studies [3,27].All these studies excluded patients who had contraindications to gadolinium contrast.The proportion of CKD patients with LGE was 40.6% (95% CI: 29.7-52.6;I2: 36.48%).Heterogeneity was moderate in the meta-analysis evaluating LGE.The forest plot of LGE is shown in Figure 5.

T1 Values in CKD
In three studies with 132 CKD patients, the pooled mean native septal T1 at 1.5 T CMR was 998.2 ms (95% CI 970.08-1026.32;I2 96.44%).A meta-analysis of two studies comparing 63 CKD patients with 75 controls was conducted, and the overall SMD of native septal T1 of CKD and controls at 1.5 T was 1.099 (95% CI: 0.73-1.46;I2 0%; p-value <0.05), suggesting a large difference with small heterogeneity between the two groups.
The forest plots are shown in Figure 6A-6B.

T2 Values in ESKD Patients
Three studies with 109 ESKD patients evaluated the T2 using single-shot SSFP in 1.5 T CMR.The mean T2 value was 50.81 ms (95% CI: 49.71-51.9;I2 84.22%), and the heterogeneity was considerable.Two studies with 53 patients evaluated the T2 using balanced SSFP in 3 T CMR.The mean T2 was 44.17

Publication bias
Based on visual inspection of the funnel plot and by using the Egger regression test, there was no evidence of publication bias in the studies (Egger's p-value=0.32).The funnel plot is shown in Figure 9.

Discussion
It has been scientifically proven by several studies, and we reinforce that patients with CKD and ESKD have increased LVMi in the presence of a preserved ejection fraction.Furthermore, there were increased T1 values and the presence of LGE, indicating an increased burden of fibrosis in this population.
Two-dimensional (2D) M-mode echocardiography overestimates left ventricular mass and has other limitations, such as interobserver variability and dependence on volume status to determine LV volume.For these reasons, multiparametric CMR analyses are increasingly utilized to assess LV function and diagnose specific cardiomyopathies [34].The cine technique with balanced SSFP is used to measure the size and mass of the LV.SSFP produces bright signals from still tissues while reducing signals from moving tissues and blood.CMR can accurately measure LVMi, providing valuable data in patients without symptomatic cardiac disease or dilated cardiomyopathy [5].
Up to 70% of ESKD patients have left ventricular hypertrophy.Since increased LVMi has been directly related to increased mortality, many studies have evaluated its relationship to dialysis.Conventional thrice-weekly hemodialysis causes LVMi regression in only approximately 50% of patients [35].The Frequent Hemodialysis Network compared six times per week to three times per week of in-center hemodialysis.The arm with six times per week of dialysis had a greater reduction in left and right ventricular systolic and diastolic volumes and mass.In the Frequent Hemodialysis Network nocturnal trial, patients with preexisting uremic cardiomyopathy had a 22% decrease in LVMi with nocturnal home HD compared to conventional HD [13].
LGE has been used due to its high sensitivity to detect diffuse myocardial fibrosis and scarring.However, its use may be limited in patients with advanced CKD due to concerns about nephrogenic systemic fibrosis.Areas of fibrosis appear brighter after gadolinium contrast administration due to the increased volume of distribution of the contrast and the prolonged washout.The presence of subendocardial LGE represents prior infarction, and diffuse fibrosis could represent changes due to uremic cardiomyopathy.Many studies in CKD and ESKD patients have shown increased LGE [32,36].A study by Schietinger et al. demonstrated the presence of LGE in 79% of hemodialysis patients.Most of these LGEs were not related to prior infarcts but were associated with dysfunctional LV segments [37].In our meta-analysis, LGE was present in more than one-third of the patients.
Native T1 values are capable of spotting early and subtle myocardial changes that are invisible to the naked eye on grayscale images.They can differentiate between normal and infarcted areas of the myocardium.This quantitative technique to detect focal fibrosis is based on the longitudinal recovery time of excited hydrogen atoms in various tissues.T1 mapping is obtained by combining a series of T1 relaxation times.This has been reliably used in the diagnosis of cardiomyopathies, quantification of areas of fibrosis, prognostic determination, and guidance of therapies [38].Several studies have reported increased T1 values in CKD and ESRD patients [39].Myocardial fibrosis unrelated to ischemia occurs early in uremic cardiomyopathy, and this increases with the severity of CKD [40].T1 mapping can be used as a surrogate biomarker to evaluate fibrosis in a non-invasive manner.Furthermore, it has been shown that elevated T1 values and biopsy-measured fibrosis had a good correlation.Qin et al. showed that T1 mapping could predict major adverse cardiac events in hemodialysis patients [23].Early detection of fibrosis could provide the necessary therapeutic interventions since systolic and diastolic function over the long term culminates in dilated cardiomyopathy and ultimately leads to congestive heart failure.Hayer et al. found that cardiac fibrosis in CKD patients without diabetes was independent of hypertension and aortic distensibility [27].Edwards et al. found that T1 values were higher in CKD patients than in hypertensive patients and healthy controls [3].Lin et al. demonstrated that ESKD patients on peritoneal dialysis with normal diastolic function had higher T1 and T2 values, and no difference in values was found between patients with or without hypertension or anemia [20].In a study by Puntmann et al., increased native T1 values were predictive of allcause mortality and heart failure in nonischemic cardiomyopathy [41].Increased iron load, genetic cardiomyopathies, lipid storage diseases, prior infarcts, cardiomyopathies due to aortic stenosis, and amyloidosis can also cause abnormal T1 values, and these studies were excluded from our meta-analysis.Increased T1 values are usually seen with 3 T scanners compared to 1.5 T scanners due to the increased magnetic field strength [42].Our meta-analysis showed increased T1 values in CKD and ESKD patients compared to controls.
T2 mapping measures the course of radiofrequency-excited hydrogen atoms and their transverse relaxation.T2 mapping has increased accuracy compared with T2-weighted imaging.Increased edema states in the myocardium cause longer T2 relaxation times, so they are indicative of the volume status of patients.They can also detect areas of inflammation and are currently utilized to diagnose myocarditis, drug and chemotherapeutic agent toxicities, and cardiac transplant rejection [5] [17].T2 mapping has been validated in myocarditis, myocardial infarction, and other cardiomyopathies [43].
The use of CMR has some limitations.CMR may not be available in all facilities, and it also requires longer examination times.It may not be suitable for claustrophobic patients, patients who have metallic intraocular implants, cochlear implants, neurostimulation systems, or other ferromagnetic objects.Despite these drawbacks, it remains a robust and accurate tool to detect LV remodeling.

Limitations
Our study has some limitations.First, since meta-analysis inherently relies on the studies included, the limitations and biases of individual studies are incorporated into the analysis.Second, most of the studies were observational studies, and some had a small sample size.Third, the timing of dialysis and the volume status varied across studies, although most studies performed CMR post-dialysis.Fourth, the presence of other co-morbidities could also contribute to fibrotic changes in the myocardium.Finally, studies were divided into 1.5 and 3 T scanners, but the use of different CMR scanners, protocols, and vendors in the studies can yield different CMR values.

Conclusions
Our meta-analysis findings suggest that the use of CMR in CKD and ESKD patients can diagnose early unfavorable LV remodeling, despite the heterogeneity in the included studies being a limitation.Myocardial LVMi and native septal T1 values are increased in CKD and ESKD compared to controls.T1 mapping can detect cardiac fibrosis in the early stages of CKD and ESKD and can help clinicians stratify subclinical disease risk.Further, large, blinded RCTs with longer follow-ups are necessary to study LV changes in detail and their relationship with dialysis.There is a need to standardize threshold values while using T1 mapping with different scanner strengths.Further studies are also needed to validate T1 and T2 mapping techniques in CKD and ESKD populations.
The inclusion criteria are as follows:(1) patients ≥18 years old with CKD stage 2 or lower (<89 ml/min/1.73m2) and ESKD; (2) results must report mean values, standard deviations, or confidence intervals (CIs) of CMR values.The exclusion criteria were as follows: (1) studies reporting CMR findings in (a) myocardial infarction, (b) hypertrophic cardiomyopathy, (c) aortic stenosis, (d) lipid storage diseases, (e) iron accumulation, (f) amyloidosis, and (g) studies evaluating the effects of spironolactone or other agents on systolic function; (2) studies evaluating CMR post-kidney transplantation; and (3) review articles and case series.

TABLE 1 : Literature search strategy
CMR measurements, and outcomes of the included studies are detailed in Table2.
[27]had increased native T1 time.However, no differences in LV mass or EF were seen.Myocardial fibrosis is increased in early CKD and 2024 Chandramohan et al.Cureus 16(1): e51672.DOI 10.7759/cureus.51672associatedwithincreased GLS.More frequent in-center hemodialysis resulted in reduced left ventricular, right ventricular endsystolic, and end-diastolic volume and mass.No changes were observed with ventricular remodeling.Approximately 3-hour sessions of HD are associated with a reduction in LV mass, attributable to a decrease in edema.T1 and T2 values decreased post-dialysis.Increased myocardial native T1 and T2 values and decreased LV global strain were found in ESKD patients with preserved LVEF compared with the healthy controls.In particular, increased myocardial T1 and T2 values were found in ESKD patients who did not show evidence of systolic or diastolic dysfunction on echocardiography.withadvancingCKD independent of effects of left 2024 Chandramohan et al.Cureus 16(1): e51672.DOI 10.7759/cureus.516725 of 19al.[27]

TABLE 2 : Patient characteristics and outcomes of 1.5 T and 3 T CMR studies included in the systematic review and meta-analysis
Values are expressed as the mean ± standard deviation or as the number (percentage) of subjects BNP: B-type natriuretic peptide; CAD: coronary artery disease; CKD: chronic kidney disease; CMR: cardiac magnetic resonance imaging; EF: ejection fraction; eGFR: estimated glomerular filtration rate; ESKD: end-stage kidney disease; HD: hemodialysis; GLS: global longitudinal strain; HFpEF: heart failure with preserved ejection fraction; LV: left ventricle; LVEF: left ventricular ejection fraction; LVMi: left ventricular mass index; NT-pro-BNP: N-terminal prohormone of brain natriuretic peptide; T1: longitudinal relaxation time; T2: transverse relaxation time; MACE: major adverse cardiac events

TABLE 4 : Quality assessment of the studies by the Newcastle-Ottawa quality assessment form
CMR: cardiac magnetic resonance imaging Heterogeneity was considerable in the meta-analysis.The forest plots are shown in Figure 2A-2D.
. Studies by Arcari et al. and Kotecha et al. showed a reduction in T2 values post-dialysis [16,19].Han et al. demonstrated that T2 values correlated with T1 values in hemodialysis patients