ABSTRACT
Background
Iron overload by liver magnetic resonance imaging (MRI) is highly prevalent today in the hemodialysis population worldwide and is a controversial topic in the management of dialysis-related anemia, as iron deposits can be seen on MRI but without clinical consequences. The aim of this study was to look for evidence of pancreatic iron deposits (a surrogate marker of severity in iron overload diseases) and their possible association with mortality.
Methods
Liver iron concentration was analyzed in 115 patients on dialysis using signal intensity ratio MRI and R2* Relaxometry MRI to determine liver, spleen, spine and pancreas iron loads.
Results
Overall, 44.3% (51/115) had liver iron overload upon MRI and 20% (23/115) of patients exhibited increased pancreatic iron load. The percentage of patients with abnormal pancreatic T2* was significantly higher in the group with moderate and severe liver iron overload [46.7% (7/15)] as compared with the groups of patients with normal iron load [15.6% (10/64)] and mild iron overload [16.7% (6/36)] (P = .032, Fisher’s exact test). Median survival time was reduced to 2.6 years in patients with pancreatic iron deposits as compared with 6.6 years in patients with normal pancreatic iron (P = .028, Log-rank test). Pancreatic iron deposits were associated with a 3-fold higher risk of death in the Cox proportional hazard regression model (hazard ratio 3.614, P = .0031).
Conclusion
Pancreatic iron deposits are observed in a substantial proportion of patients on dialysis with moderate and severe liver iron overload and may be associated with an increased risk of mortality.
Trial registration: ClinicalTrials.gov number NCT05593068.
Keywords: dialysis, iron overload, mortality, pancreatic iron deposits, T2* MRI
Graphical Abstract
Graphical Abstract.
KEY LEARNING POINTS.
What was known:
Iron overload (due to the use of intravenous iron) by liver magnetic resonance imaging (MRI) is highly prevalent today in the dialysis population (affecting up to 70% of patients) and is a controversial issue in the management of dialysis-related anemia, because iron deposits can be seen on MRI but without clinical consequences.
This study adds:
This study used data from a sample of adult patients on dialysis followed by MRI and found that pancreatic iron deposits (a surrogate marker of severity in hemosiderosis) are encountered in a substantial percentage of patients and are associated with a reduced survival and an increased risk of death.
Potential impact:
This study shows for the first time that iron deposition by MRI in end-stage kidney disease (ESKD) may be associated with adverse clinical outcomes.
These findings may have important implications for current clinical practice and guidelines for the management of anemia and iron therapy in ESKD and will foster debate on iron metabolism in dialysis.
INTRODUCTION
Since the discovery of recombinant human erythropoietin in the 1980s, treatment of anemia in patients with end-stage kidney disease (ESKD) has mostly been based on the routine use of recombinant erythropoiesis-stimulating agents (ESAs) combined with parenteral iron products. This combination is used to ensure efficient erythropoiesis on ESA and to overcome true and functional iron deficiency, a frequent complication in this setting [1]. In the pre-ESA era, iron overload was highly prevalent and clinically severe among dialysis patients due to the need for multiple blood transfusions to maintain sufficient hemoglobin levels for survival [1]. Iron overload identified by quantitative liver magnetic resonance imaging (qMRI) is highly prevalent today in the hemodialysis population worldwide (affecting up to 70% of patients studied by MRI in a recent meta-analysis) [2–5]. In patients on dialysis, iron accumulation in the liver increases hepcidin production [3, 4], which has been associated in epidemiological studies with an increased risk of cardiovascular events and mortality in this setting [6, 7]. Furthermore, it has been demonstrated using MRI that excessive liver iron deposits decrease in patients on dialysis following ESA administration after and intravenous (IV) iron withdrawal within approximately 1 year [3, 4], while those patients with severe iron overload have recently shown improvement on MRI from the addition of chelators (deferoxamine and deferasirox) [8, 9].
Therefore, iron overload has become one of the most controversial topics in the management of dialysis-related anemia, as iron deposits can be seen on MRI but without clinical consequences [10].
The presence of pancreatic iron deposits found using R2* Relaxometry MRI is universally considered as a surrogate marker of severity in iron overload diseases [11, 12] and is associated with cardiac involvement, diabetes mellitus and mortality in secondary hemosiderosis, especially in thalassemia [13–15].
The aim of this study was therefore to analyze evidence of pancreatic iron deposits and their potential association with mortality in a cohort of patients on dialysis studied by qMRI.
MATERIALS AND METHODS
Ethics
In accordance with French rules and regulations, clearance from an ethics committee for this retrospective observational study was not required. This study falls within the framework of the MR-004 reference methodology defined by Commission Nationale de l’Informatique et des Libertés, France’s authority for protecting data privacy. The study was registered on the French public Health Data Hub (F20230109205346) after being approved by the scientific college of the Ramsay Health Cooperation Group for Education and Research, which was responsible for this study (COS-RGDS-2018-12-013). The study was also registered on ClinicalTrials.gov (NCT05593068). All participants gave informed oral consent.
Study design
All patients belonged to the “Cohort study of dialysis patients based on hepatic magnetic resonance imaging,” established by Claude Galien Hospital. This was a prospective, cross-sectional and longitudinal study between 31 January 2005 and 29 February 2020. Its aim was to study iron stores by MRI and their possible causes in patients treated by dialysis. The study received technical and ethical approval from the Drug, Devices and Clinical Trials Committee of our institution (COMEDIMS Claude Galien, 9 December 2004 and 15 February 2013), and was registered under International Standard Randomised Controlled Trial (ISRCTN): 80 100 088 [4, 16].
From this study, we devised a second “targeted study” to analyze iron deposits by MRI in the pancreas (primary goal), as well as in the spleen, heart and bone marrow (secondary goals) and their possible causes and potential consequences in patients with ESKD treated by dialysis (Fig. 1). Inclusion criteria were as follows: male or female patients of 18 years of age or older who were treated by dialysis at the Claude Galien Hospital and who underwent one (or more) abdominal MRI for iron quantification.
Figure 1:
Flowchart of the study.
Exclusion criteria were as follows: pregnant women, poor compliance with dialysis technique, severe cognitive impairment, cirrhosis of the liver, inflammatory syndrome or ongoing infectious disease, genetic hemochromatosis and transfusional-related hemosiderosis associated with hemoglobinopathies and hematological diseases, recent major bleeding and recent major surgery, blood transfusion dependency, progressive malignant disease. This study was conducted using the MRI imagery bank stored on specific General Electric servers at the division of Radiology of Claude Galien Hospital, Quincy, France. Results of R2* Relaxometry MRI of bone marrow have recently been published [17].
MRI estimation of hepatic iron stores
We used a signal intensity ratio (SIR) method based on T1 and T2* contrast imaging without gadolinium, as described in Gandon et al. [18]. Liver iron load, determined by R2* Relaxometry MRI as described by Wood et al. [19], was used during the same radiological session to validate liver iron concentration (LIC) values determined by SIR since 2012 and was expressed in T2* in ms. Splenic iron load was also assessed by R2* Relaxometry MRI as described by Wood et al. [19], during the same session and expressed in T2* in ms since 2012. Normal splenic iron concentration was set at T2* >15 ms, consistent with Schwenzer et al. [20].
Estimation of bone marrow iron stores and pancreatic iron load by R2* Relaxometry MRI
Bone marrow iron stores and pancreatic iron deposits were analyzed retrospectively using the bank of MRIs stored on specific GE servers at the division of radiology of Claude Galien Hospital by a specialist MRI technician (S.F.) working with an experienced radiologist (Y.C.). The images were post-processed manually at the MRI console using the software provided by the manufacturer (GE Medical Systems, Milwaukee, WI, USA) to generate T2*/R2* maps. First, the technician and the radiologist chose the best image of vertebrae and of the pancreatic region (including body and head) on axial slices and determined one region of interest (ROI) on the image. The size of the ROI was variable but had to be at least 1 cm2 for vertebrae (as suggested by Papakonstantinou et al. [21] and Regenboog et al. [22]) and for the pancreas (as suggested by Schwenzer et al. [20] and Restaino et al. [23]).
Anemia treatment and iron therapy
Treatment of anemia in these patients was carried out according to usual clinical practices. It followed the European Renal Best Practice (ERBP) 2009 and thereafter 2013 anemia statements and comprised, when required, ESA for patients treated by hemodialysis and peritoneal dialysis and IV iron for patients on hemodialysis [24, 25]. Oral iron was used as first-line therapy only in patients treated by peritoneal dialysis [25].
Biological markers for follow-up of ESA and iron therapies
Monthly measurements of iron biomarkers (ferritin, transferrin, serum iron, transferrin saturation, reticulocyte hemoglobin content) and C-reactive protein (CRP) were also performed routinely in both patients treated by hemodialysis and by peritoneal dialysis. In order to further analyze the role of inflammation as a contributor or as a consequence of iron overload, we calculated the neutrophil-to-lymphocyte (NLR), monocyte-to-lymphocyte (MLR), platelet-to-lymphocyte (PLR) and neutrophil-to-monocyte (NMR) ratios for each group of patients [26, 27].
French registry of dialysis patients
The Renal Epidemiology and Information Network (REIN, French registry) tracks all the patients of all ages in France treated for ESKD by a renal replacement technique (hemodialysis, peritoneal dialysis or transplantation). It gives access to the actual status of patients previously treated by kidney replacement technique as alive still in dialysis, alive and on the waiting list for a transplant (with a specific date of grafting) or deceased (with a specific date and cause of death).
Statistical analysis
Since most of our data did not have a Gaussian distribution, all data are expressed as median and first quartile (Q1) and third quartile (Q3) values [28]. Percentages are given either in gross values or with 95% confidence intervals (CI) using the modified Wald method [28]. Patients with moderate liver iron overload and those with severe iron overload were pooled together for all statistical analyses.
The groups of patients were compared using non-parametric analysis of variance with the Kruskal–Wallis test, followed by Dunn’s post-test. The groups of patients were compared with either the Chi-square test or the Fisher’s exact test (depending on the size of the samples) for categorical variables [28]. Correlations between the different variables were analyzed by calculating Spearman’s rank-order correlation coefficient [28].
We also determined the percentage and number of patients in each dialysis group who had increased pancreas iron load as evidenced by pancreatic T2* lower than 25 ms, as proposed by Ghoti et al. [3] extrapolating the lower limit of normal pancreas T2* in two cohorts of healthy individuals studied by Schwenzer et al. [20] and Restaino et al. [23] and compared them using the Fisher’s exact test [28]. Prism 10.2.2 software (GraphPad, San Diego, CA, USA) was used for all tests, and P-values <.05 were considered to denote statistical significance [28].
Binary logistic regression analysis using the Wald test was used to determine the capacity of several clinical and biological relevant variables to classify patients as having normal pancreas iron content (defined as ≥25 ms at pancreatic T2*) or elevated pancreas iron content (defined as <25 ms at pancreatic T2*) and to classify patients as having normal (≤50 µmol/g) or increased LIC (>50 µmol/g) by SIR-MRI (SPSS 26 software, IBM, Bois-Colombes, France) [28].
Kaplan–Meier analyses with the Log-rank test were used to compare the overall survival rates between the patients on dialysis with normal pancreatic iron load and those having pancreatic iron deposits (SPSS 26 software, IBM, Bois-Colombes, France) [28].
The multivariate Cox proportional hazards regression model was used to assess the associations between the explanatory variables and survival in this cohort of patients treated by dialysis (SPSS 26 software, IBM, Bois-Colombes, France) [28]. Of note, with regard to the impact of gender in this model, the reference group was the female group; in order to analyze the influence of diabetes mellitus in this model, the reference group was the group of patients without diabetes.
Finally, since our total population comprised 115 patients, a figure higher than the minimal sample of 100 patients for meaningful results in this setting, we did not perform sample size calculation, given the complexity of such analyses [28] and also given uncertain hypotheses based on findings by Ghoti et al. in highly iron-overloaded patients with only a small sample of patients studied for pancreatic iron deposits (8 out 21 patients, 3 of them with pancreatic iron deposits) [3].
RESULTS
Characteristics of the study population
The study cohort comprised 115 adult patients with ESKD treated by dialysis at Claude Galien Hospital (N = 106 by hemodialysis; N = 9 by peritoneal dialysis), analyzed by R2* Relaxometry since 2014. The demographic, clinical and biological characteristics of these patients are shown in Tables 1 and 2.
Table 1:
Characteristics of the 115 patients treated by dialysis and clinical findings.
| Normal liver iron LIC ≤50 μmol/g, Group A (N = 64) | Mild iron overload 50 < LIC ≤ 100 μmol/g, Group B (N = 36) | Moderate and severe iron overload LIC >100 μmol/g, Group C (N = 15) | P-valuea | Comparison of groups A, B, Cb | |
|---|---|---|---|---|---|
| Age (years) | 66 (56.3–75.8) | 59.5 (45.5–77.8) | 66 (55–86) | .36 | |
| Sex, n (%) | |||||
| Female | 20 (31.3) | 12 (33.3) | 10 (66.7) | .033 | |
| Male | 44 (68.8) | 24 (66.7) | 5 (33.3) | ||
| BMI (kg/m2) | 26 (23.3–30.8) | 24.5 (21.3–28) | 27 (23–30) | .12 | |
| Diabetes, n (%) | 28 (43.8) | 13 (36.1) | 4 (26.7) | .43 | |
| Modified Charlson’s Comorbidity Index | 6 (4–8) | 5.5 (3.3–7) | 7 (3–8) | .20 | |
| AUDIT alcohol index | 2 (0.3–3.8) | 1 (0–4) | 2 (0.8–3) | .91 | |
| Missing values | 12 | 5 | 1 | ||
| Time spent on dialysis before MRI (months) | 6.5 (3.2–30.4) | 28.9 (13.6–50.3) | 18.1 (15–52.3) | <.0001 | A/B P = .0001 |
| A/C P = .029 | |||||
| B/C P > .99 | |||||
| Follow-up after MRI (month) | 28.5 (13.5–53.5) | 31 (9–53.5) | 32 (16–59) | .82 | |
| ESA therapy, n (%) | 55 (85.9) | 30 (83.3) | 13 (86.7) | .93 | |
| Darbepoetin dose in the month of the MRI (μg/week) | 35 (20–57.5) | 30 (12.5–50) | 40 (10–60) | .57 | |
| Oral iron therapy, n (%) | 19 (32.8) | 14 (46.7) | 0 (0) | .044 | |
| Missing values | 6 | 6 | 7 | ||
| Oral iron therapy dose (mg/month) | 0 (0–10.5) | 0 (0–37) | 0 (0–0) | .058 | |
| Transfused patients, n (%) | 18 (30.5) | 8 (27.6) | 3 (37.5) | .86 | |
| Iron in RBC packs transfused (mg/month) | 47 (24–112.5) | 32 (15.3–33) | 87 (33–136) | .13 | |
| IV iron therapy, n (%) | 40 (67.8) | 29 (96.7) | 8 (100) | .0020 | |
| Missing values | 5 | 6 | 7 | ||
| IV iron dose (mg/month) | 120 (0–241) | 197.5 (153–268.3) | 231 (192.8–392.3) | .0031 | A/B P = .023 |
| A/C P = .029 | |||||
| B/C P > .99 | |||||
| Iron total receivedc (mg/month) | 176 (0–300) | 229 (187.3–295.8) | 274.5 (192.8–501.8) | .039 | A/B P = .17 |
| A/C P = .13 | |||||
| B/C P > .99 | |||||
| Liver iron content (µmol/g dry weight) | 30 (24.3–35.8) | 65 (60–81.5) | 190 (150–240) | <.0001 | A/B P < .0001 |
| A/C P < .0001 | |||||
| B/C P = .038 | |||||
| Liver T2* (ms) | 24.5 (19.1–30.2) | 10.2 (9–12.7) | 6.9 (5.4–8.1) | <.00001 | A/B P < .0001 |
| A/C P < .0001 | |||||
| B/C P = .065 | |||||
| Pancreas T2* (ms) | 34 (28.8–41.3) | 33.8 (28.8–36.3) | 27 (23.8–25.3) | .051 | A/B P > .99 |
| A/C P = .045 | |||||
| B/C P = .28 | |||||
| Pancreas T2*, n (%) abnormal <25 ms | 10 (15.6) | 6 (16.7) | 7 (46.7) | .032 | |
| Splenic T2* (ms) | 26.3(15.2–38.1) | 15.3 (8–26.2) | 5.9 (4.3–15.4) | <.0001 | A/B P = .019 |
| A/C P < .0001 | |||||
| B/C P = .018 | |||||
| Missing values | 1 | 0 | 0 | ||
| Vertebral T2* (ms) | 12.5 (10.3–17.3) | 9.9 (7.3–15.1) | 5.95 (5.3–12.5) | .0001 | A/B P = .034 |
| A/C P = .0002 | |||||
| B/C P = .12 | |||||
| Missing values | 5 | 1 | 1 |
The patients were monitored simultaneously for liver iron and pancreatic iron and were classified according to hepatic non-heme iron stores measured by MRI. Percentages are presented for binary variables. Percentages, medians and interquartile ranges are based on data from the available number of cases per variable.
a,b P-value determined using either: aKruskal–Wallis, Chi-square or Fisher’s exact test and bDunn’s post test.
cIron total received is the cumulative amount of iron received by IV + oral treatments + iron in RBC transfusions.
Iron in RBC packs transfused, we calculate 200 mg of iron per RBC packs transfused and we report per month of dialysis. For oral iron, we considered that 10% of prescribed dose in mg was absorbed.
RBC, red blood cell; BMI, body mass index.
Table 2:
Biochemical markers of iron metabolism and inflammation in 115 patients treated by dialysis.
| Normal liver iron LIC ≤50 μmol/g, Group A (N = 64) | Mild iron overload 50 < LIC ≤ 100 μmol/g, Group B (N = 36) | Moderate and severe iron overload LIC >100 μmol/g, Group C (N = 15) | P-valuea | Comparisons of Groups A, B, Cb | |
|---|---|---|---|---|---|
| Hemoglobin (g/dL) | 10.8 (9.6–11.7) | 11.3 (10.5–12.5) | 11.4 (9.8–12.5) | .13 | |
| Missing values | 0 | 0 | 0 | ||
| Hematocrit (%) | 33 (30.4–36.8) | 35.4 (33.1–38.9) | 36.3 (31.2–38.4) | .046 | A/B P = .048 |
| A/C P = .67 | |||||
| B/C P > .99 | |||||
| Missing values | 1 | 0 | 0 | ||
| CHR (pg) | 30.7 (28.3–32.5) | 31.4 (29–32.8) | 30.3 (28.2–31.8) | .67 | |
| Missing values | 5 | 4 | 1 | ||
| NLR | 2.85 (1.94–4.03) | 2.57 (1.62–3.40) | 3.44 (1.91–5.26) | .20 | |
| Missing values | 2 | 0 | 0 | ||
| MLR | 0.37 (0.25–0.52) | 0.31 (0.22–0.46) | 0.31 (0.22–0.60) | .29 | |
| Missing values | 2 | 0 | 0 | ||
| PLR | 149 (112.6–221.8) | 150.6 (111.9–193.6) | 144.1 (131.1–274) | .79 | |
| Missing values | 2 | 0 | 0 | ||
| NMR | 7.17 (5.90–9.64) | 7.78 (5.54–10.52) | 11.03 (8.74–13.08) | .011 | A/B P > .99 |
| A/C P = .011 | |||||
| B/C P = .022 | |||||
| Missing values | 2 | 0 | 0 | ||
| CRP (mg/L) | 4.2 (2–9.4) | 3.4 (1.2–6.3) | 5.8 (3.5–13.3) | .17 | |
| Missing values | 0 | 0 | 0 | ||
| Serum ferritin (ng/mL) | 123 (59–271.3) | 183.5 (76.3–470.8) | 404 (117–785) | .0060 | A/B P = .22 |
| A/C P = .0073 | |||||
| B/C P = .32 | |||||
| Missing values | 1 | 0 | 0 | ||
| Serum iron (µmoL/L) | 9.2 (6.7–12.4) | 9.7 (7–13.6) | 9.9 (8–15.7) | .58 | |
| Missing values | 1 | 0 | 0 | ||
| Serum transferrin (g/L) | 2 (1.7–2.4) | 2 (1.5–2.3) | 1.7 (1.6–1.9) | .047 | A/B P = .76 |
| A/C P = .047 | |||||
| B/C P = .42 | |||||
| Missing values | 1 | 0 | 0 | ||
| TotaL iron-binding capacity (μmoL/L) | 50 (42.5–60) | 50 (38.5–57.5) | 42.5 (40–47.5) | .042 | A/B P = .71 |
| A/C P = .042 | |||||
| B/C P = .41 | |||||
| Missing values | 2 | 0 | 0 | ||
| Transferrin saturation (%) | 18.5 (14.2–25.2) | 19.7 (14.1–32.2) | 23.4 (19.8–39.3) | .11 | |
| Missing values | 1 | 0 | 0 | ||
| Albumin (g/L) | 35 (33–39) | 39 (36–42.8) | 37 (34–40) | .0026 | A/B P = .0017 |
| A/C P > .99 | |||||
| B/C P = .37 | |||||
| Missing values | 1 | 0 | 0 | ||
| Prealbumin (g/L) | 0.32 (0.26–0.37) | 0.34 (0.26–0.39) | 0.32 (0.27–0.39) | .92 | |
| Missing values | 2 | 0 | 0 | ||
| HbA1c (%) | 5.6 (5.2–6.3) | 5.5 (4.9–6.3) | 5.5 (4.7–6) | .50 | |
| Without diabetes | 5.3 (4.9–5.5) | 5.3 (4.8–5.6) | 4.8 (4.7–5.6) | .84 | |
| Diabetes | 6.3 (6.1–6.8) | 6.8 (5.5–7.9) | 6.7 (5.6–8) | .77 | |
| Missing values | 1 | 1 | 0 | ||
| ASAT (U/L) | 15 (10.5–19) | 13.5 (10–18.8) | 13 (12–18) | .87 | |
| Missing values | 3 | 0 | 0 | ||
| ALAT (U/L) | 11 (8–18) | 13.5 (10–24) | 15 (8–19) | .47 | |
| Missing values | 1 | 0 | 0 | ||
| GGT (U/L) | 24 (16–60) | 21 (13–35) | 26 (22–40) | .34 | |
| Missing values | 1 | 1 | 0 |
The patients were monitored simultaneously for liver iron and pancreatic iron and were classified according to hepatic non-heme iron stores measured by MRI. All values shown are median and interquartile ranges.
a,b P-value determined using either: aKruskal–Wallis or bDunn’s post test.
CHR, reticulocyte hemoglobin content; HbA1c, glycated hemoglobin; ASAT, aspartate aminotransferase; ALAT, alanine aminotransferase; GGT, gamma-glutamyl transferase.
Hepatic and spleen iron load by MRI
All the patients in this study (N = 115) underwent, during the same radiological session, an SIR-MRI exam combined with a R2* Relaxometry exam. LIC was normal (≤50 µmol/g) in 55.7% (64/115) of patients (95% CI 46.5–64.4). Iron overload was mild (50 < LIC ≤ 100 µmol/g) in 31.3% (36/115) of patients (95% CI 23.5–40.3). A total of 13% (15/115) of patients (95% CI 8–20.5) on dialysis had either moderate (N = 9; 100 < LIC ≤ 200 µmol/g) or severe (N = 6; LIC >200 µmol/g) iron overload by MRI (Table 1).
Values of LIC at SIR-MRI were significantly associated at Spearman’s correlation test with liver T2* values at R2* Relaxometry MRI (rho = –0.896, P < .001), vertebral T2* values at R2* Relaxometry MRI (rho = –0.396, P < .001) and pancreatic T2* values at R2* Relaxometry MRI (rho = –0.184, P = .049).
Most patients with liver iron overload also had decreased splenic T2*, indicating concomitant excess iron in the spleen (Table 1). Percentage of abnormal splenic iron (<15 ms) was 38.6% (44/114) (95% CI 30.2–47.8). Values of spleen T2* were significantly associated with liver iron concentration at SIR-MRI (rho = –0.508, P < .001, Spearman’s correlation test) and with liver T2* values at MRI (rho = 0.481, P < .001, Spearman’s correlation test).
In moderate and severe liver iron overload, as compared with normal LIC or mild iron overload, values of NLR and NMR were found to be statistically increased, whereas CRP showed only a non-significant trend towards higher levels (Table 2).
Determinants of liver iron content
LIC correlated with several iron biomarkers upon Spearman’s correlation test, namely serum ferritin (rho = 0.348, P < .001), hematocrit (rho = 0.225, P = .016), transferrin saturation (rho = 0.196, P = .037), serum transferrin (rho = –0.255, P = .0062), total iron-binding capacity (rho = –0.264, P = .0048) and albumin (rho = 0.249, P = .0076), and with demographic characteristics, namely the time spent on dialysis (rho = 0.377, P < .001), and with parenteral iron received per month (rho = 0.484, P < .001) and total iron received per month (rho = 0.363, P < .001).
Upon binary logistic regression analysis, seven variables accurately classified the patients into those with normal LIC (≤50 µmol/g) and those with increased LIC (>50 µmol/g) at Wald test, namely the time spent on dialysis before MRI [odds ratio (OR) 1.023 (95% CI 1.002–1.044); P = .033], total iron dose per month [OR 1.008 (95% CI 1.003–1.013); P = .0022], the modified Charlson’s Comorbidity Index [OR 0.795 (95% CI 0.638–0.990); P = .041], spleen T2* [OR 0.956 (95% CI 0.917–0.997); P = .037], vertebral T2* [OR 0.879 (95% CI 0.775–0.997); P = .044], pancreas T2* [OR 0.935 (95% CI 0.881–0.991); P = .025] and body mass index [OR 0.881 (95% CI 0.782–0.993); P = .038].
Pancreatic iron load by R2* Relaxometry MRI
All patients had a measurement of the body of the pancreas while only 38 patients also had concurrent measurement of the head of the pancreas. T2* values did not differ in these 38 pairs of patients between these two anatomical parts of the pancreas [body, 34.05 ms (29.6 to 42.2); head, 35.50 ms (29.0 to 51.3); P = .25 at Wilcoxon rank test].
The percentage of patients with abnormal pancreatic T2* measure (values <25 ms) was significantly higher in the group with moderate and severe liver iron overload by qMRI [46.7% (7/115), 95% CI 24.8–69.9] as compared with the groups of patients with normal iron load [15.6% (10/64), 95% CI 8.5–26.6] and mild iron overload [16.7% (6/36), 95% CI 7.5–32.3]; P = .032, Fisher’s exact test (Table 1, Fig. 2).
Figure 2:
Histogram of abnormal pancreatic T2* at MRI translating excess iron load in pancreas in 115 patients on dialysis. Abnormal pancreas T2* (<25 ms) in patients classified according to liver non-heme iron stores measured by MRI with normal iron load (LIC ≤ 50 μmol/g, N = 64), mild liver iron overload (50 < LIC ≤ 100 μmol/g, N = 36) and moderate and severe liver iron overload (LIC > 100 μmol/g, N = 15). In 15.6% of cases (10/64), patients have been found to have abnormal pancreatic T2* values (<25 ms) in conjunction with a normal hepatic iron load. Six of 36 (16.7%) of patients exhibited an abnormal pancreatic T2*, in the presence of a mild hepatic iron load. Similarly, 7/15 (46.7%) of patients exhibited an abnormal pancreatic T2*, in the presence of a moderate-to-severe hepatic iron load (P = .032, Fisher’s exact test). Data are expressed in percentage of patients.
Pancreatic iron load differed significantly between patients classified according to hepatic non-heme iron stores and having simultaneously abnormal pancreatic T2* values: those with moderate or severe iron overload by qMRI (N = 7) had greater increased in pancreatic iron load at R2* Relaxometry MRI [T2* = 20 ms (range 17.1–23.3)] when compared with patients with normal liver iron load (N = 10) [pancreas T2* = 23.55 ms (range 18–24.2)], while patients with mild iron overload (N = 6) had intermediate pancreas T2* values [21.4 ms (range 14.6–22.4)]; P = .018, Kruskal–Wallis test.
Relationship between pancreatic iron load assessed by R2* Relaxometry and hepatic, splenic and vertebral iron contents
Pancreatic T2* correlated upon Spearman’s correlation test with LIC (rho = –0.184, P = .049), liver T2* (rho = 0.218, P = .019) and with vertebral T2* (rho = 0.208, P = .031) but not with spleen iron load at R2* Relaxometry MRI (rho = 0.084, P = .37).
Other determinants of pancreatic iron load assessed by R2* Relaxometry
Besides LIC, liver T2* and vertebral T2*, pancreatic T2* correlated upon Spearman’s correlation test with age (rho = –0.234, P = .012), hemoglobin (rho = –0.240, P = .0099) and hematocrit (rho = –0.242, P = .0094).
In binary logistic regression analysis, only three variables accurately classified patients on dialysis into those with normal pancreatic iron load and those with increased pancreas iron content, namely LIC [OR 1.011 (95% CI 1.001–1.021); P = .025], the modified Charlson’s Comorbidity Index [OR 1.272 (95% CI 1.018–1.590); P = .034] and the Darbepoetin dose per week [OR 0.966 (95% CI 0.940–0.993); P = .013, Wald test].
Survival analysis of the studied patients according to the presence of iron pancreatic deposits
The gross percentage of deaths in patients with abnormal pancreas T2* was 65.2% (15/23) compared with 37% (34/92) in patients with normal pancreatic T2* (P = .019 at Fisher’s exact test). The number of deaths and the underlying reasons for each are shown in Table 3.
Table 3:
Number and causes of death on patients included in the study.
| Cohort study | Pancreas T2* abnormal | Pancreas T2* normal | |
|---|---|---|---|
| N = 115 | N = 23 | N = 92 | |
| Number of deaths, n (%) | 49 (42.6) | 15 (65.2) | 34 (37) |
| Cause of death, n (%) | |||
| Cardiovascular disease | 31 (63.3) | 9 (60) | 22 (64.7) |
| Infectious disease | 10 (20.4) | 3 (20) | 7 (20.6) |
| Cancer | 4 (8.2) | 1 (6.7) | 3 (8.8) |
| Neurological disease | 1 (2) | 1 (6.7) | 0 (0) |
| Other | 3 (6.1) | 1 (6.7) | 2 (5.9) |
| Chronic respiratory insufficiency | 1 | 1 | |
| Pulmonary arterial hypertension | 1 | 1 | |
| Unknown cause | 1 | 1 |
n, number of patients deaths and cause of death by group of patients.
In the survival analysis of our 115 patients at the time when this observational study ended (30 September 2023), the uncensored patients are represented by the 49 deceased patients, while the 66 censored patients are represented by the 30 patients who were still alive at the end of the study (still on dialysis on that date), the 33 transplanted patients and the 3 patients who had been transferred to another dialysis centre. It should be noted that follow-up of transplant patients is stopped on the day of the graft, while follow-up of transferred patients is stopped on the date of transfer.
Survival analysis with the Kaplan–Meier curve (with the point of beginning studied at the time of MRI exam and based on the data of the register REIN) showed a very significant difference in the median survival time, which reached 6.6 years in patients with normal pancreatic iron load but was reduced to 2.6 years in patients with pancreatic iron deposits (Chi-square: 4.808, P = .028, Log-rank test) (Fig. 3).
Figure 3:
Survival analysis in 115 patients on dialysis analyzed by Kaplan–Meier curve. The survival analysis compares patients with and without pancreatic iron deposits at R2* Relaxometry. The observation started at the date of the MRI and ended on 30 September 2023. The curves represent the proportion of survival (%) as a function of the time (years) between the date of the MRI until the end of the observation (upticks designate censored data). Log-rank test was used to compare the survival and to give P-value (Chi-square 4.808, P = .028).
The Cox proportional hazards regression model identified five variables associated with the risk of mortality in this cohort of patients on dialysis. First, the model identified three demographic variables usually seen in studies on dialysis: male patients were found to have a higher risk rating than the female group [hazard ratio (HR) 3.669, P = .0028] when taking in account the other studied variables. Similarly, patients with diabetes mellitus compared with non-diabetic patients (HR 2.733, P = .016), and age (per supplementary year) (HR 1.069, P = .0010) had increased risk of death, when taking account the other studied variables. Secondly, two variables related to IV iron therapy were also identified, namely abnormal pancreatic T2* (HR 3.614, P = .0031), and total iron dose per month (per supplementary mg/month) (HR 1.003, P = .038) (Table 4, Fig. 4).
Table 4:
Cox proportional hazards regression model.
| Multivariate analysis (n = 92 observations)a | ||
|---|---|---|
| Parameters | HR (95% CI) | P-value |
| Age (years) | 1.069 (1.027–1.112) | .0010 |
| BMI (kg/m2) | 0.992 (0.918–1.072) | .83 |
| Modified Charlson’s Comorbidity Index | 1.042 (0.830–1.309) | .72 |
| Hemoglobin (g/dL) | 0.765 (0.578–1.013) | .062 |
| Splenic T2* (ms) | 0.973 (0.944–1.004) | .090 |
| Vertebral T2* (ms) | 0.989 (0.912–1.072) | .78 |
| Iron total receivedb (mg/month) | 1.003 (1.000–1.006) | .038 |
| LIC (µmol/g dry weight) | 0.994 (0.987–1.001) | .10 |
| Sexc (reference group: female) | 3.669 (1.566–8.594) | .0028 |
| Diabetesd (reference: patients without diabetes) | 2.733 (1.204–6.202) | .016 |
| Pancreas (reference: normal T2* ≥25 ms) | 3.614 (1.542–8.470) | .0031 |
The multivariable analysis shows the effect of five variables on the risk of death in 115 patients on dialysis. The HR is the estimate rate of the hazard in the group with abnormal Pancreas T2* (<25 ms) versus the group with normal Pancreas T2* (≥25 ms). The proportionality assumption has been verified for all risk factors.
Twenty-three patients were excluded from the analysis due to at least one missing data element.
Iron total received is the cumulative amount of iron received by IV + oral treatments + iron in RBC transfusions.
cTo analyze the influence of sex, the reference group was taken to be the female group.
dTo analyze the influence of diabetes mellitus, the reference group was defined as the group of patients without diabetes.
BMI, body mass index; RBC, red blood cell.
Figure 4:
Figures on Cox proportional hazards regression model. Cox proportional hazards regression shows the effect of variables on the risk of event in each group of Pancreas T2*. (A) Curves with normal and abnormal Pancreas T2* show the influence of the variables female sex with diabetes mellitus on the Cox model. (B) Curves with normal and abnormal Pancreas T2* show the influence of the variables female sex without diabetes mellitus on the Cox model. (C) Curves with normal and abnormal Pancreas T2* show the influence of the variables male sex with diabetes mellitus on the Cox model. (D) Curves with normal and abnormal Pancreas T2* show the influence of the variables male sex without diabetes mellitus on the Cox model.
DISCUSSION
Pancreatic iron deposits were observed in this study in a substantial proportion of patients with moderate and severe liver iron overload by MRI. Abnormal pancreatic iron load was also encountered in patients with mild or even normal LIC, due to the large use of IV iron products in this population. We recently observed a similar phenomenon for bone marrow iron assessed by vertebral T2* [17]. Pancreatic iron deposits are typically observed in cases of genetic hemochromatosis and secondary hemosiderosis (most commonly associated with thalassemia and sickle cell disease) in instances of substantial iron overload. In such scenarios, the liver (and the spleen in these latter diseases)—the primary organs responsible for iron storage in humans—are unable to adequately buffer the excess iron within the body. The pancreas constitutes an environment conducive to the accumulation of extra-hepatic iron, a process that is facilitated by L-type calcium channels. These channels promote the entry of iron in this particular organ [11, 14]. The presence of iron deposits in the pancreas has been demonstrated to induce alterations in the functionality of beta cells with impaired insulin release, which, in the long term, can ultimately result in the demise of these cells and the subsequent onset of diabetes mellitus [11, 14].
Finally, the observed increase in NLR and NMR indicates the presence of a micro-inflammatory state in patients with moderate to severe liver iron overload. This finding aligns with the documented increase in oxidative stress observed in individuals with genetic hemochromatosis and secondary hemosiderosis associated with hematological disease [11], as well as in patients on dialysis with ferritin levels exceeding 290 ng/mL [29].
This study in a cohort of 115 patients on dialysis, with iatrogenic iron overload in about one half of them, confirms and extends the preliminary findings by Ghoti et al. who found pancreatic iron deposits in three out of eight highly iron-overloaded dialysis patients [3]. Further, this study confirms the interest of studying pancreatic iron load, as suggested in a recent conference held on the topic of iron overload in dialysis [30]. Most importantly, this study shows an association between iron pancreatic deposits in patients on dialysis and a reduced survival time of about 4 years, together with a risk of death increased by 3-fold. These results seem transposable in Europe, where a medium intensity use of IV iron products, notably in France [31, 32], is routinely seen in the anemia treatment of patients on hemodialysis, and even in North America, where higher doses of IV iron are used in this setting [33, 34]. Therefore, these findings suggest the interest of an extended use of MRI to monitor body iron stores in ESKD [35], as the use of third-generation IV iron products (ferric derisomaltose iron and carboxymaltose). Indeed, these new iron products are less prone to deposit in the liver and the spleen and show a better pharmacokinetic to bone marrow [36, 37] and these third-generation IV iron products have recently been advocated by the new UK guideline for management of anemia in chronic kidney disease to lessen the risk of iron overload in this setting [38].
The primary limitation of our study pertains to its design, which was cross-sectional and prospective but based on a retrospective analysis of MRIs over a long time period, encompassing a limited number of patients with moderate to severe iron overload. This analysis may further be limited by the potential variation in patient characteristics and anemia treatment over time, and by the recruitment of all patients at a single dialysis center in a French hospital, which may limit the generalizability of the findings. Finally, readers should keep in mind that correlation found in epidemiological studies does not necessarily imply a cause and consequence relationship.
CONCLUSION
In conclusion, pancreatic iron deposits are encountered in a substantial percentage of patients on dialysis and may be associated with a reduced survival and an increased risk of death. These findings may have important implications for current clinical practices and guidelines on ESKD anemia management and iron therapy.
ACKNOWLEDGEMENTS
The authors thank Vincent Le Coz and Anthony Saber of Newmed Publishing Ltd for proofreading our original manuscript and helping with English language editing. They also thank Tanguy Cariou and Antoine Giraud of Horiana Ltd for validating multivariate statistical analyses, survival analyses and Cox proportional hazard model.
Contributor Information
Guy Rostoker, Department of Nephrology and Dialysis, Ramsay Health Care, Claude Galien Private Hospital, Quincy-sous-Sénart, France; Collège de Médecine des Hôpitaux de Paris, Paris, France.
Mireille Griuncelli, Department of Nephrology and Dialysis, Ramsay Health Care, Claude Galien Private Hospital, Quincy-sous-Sénart, France.
Sergio Francisco, Department of Radiology, Ramsay Health Care, Claude Galien Private Hospital, Quincy-sous-Sénart, France.
Christelle Loridon, Department of Nephrology and Dialysis, Ramsay Health Care, Claude Galien Private Hospital, Quincy-sous-Sénart, France.
Eva Languille-Llitjos, Department of Nephrology and Dialysis, Ramsay Health Care, Claude Galien Private Hospital, Quincy-sous-Sénart, France.
Ghada Boulahia, Department of Nephrology and Dialysis, Ramsay Health Care, Claude Galien Private Hospital, Quincy-sous-Sénart, France.
Yves Cohen, Department of Radiology, Ramsay Health Care, Claude Galien Private Hospital, Quincy-sous-Sénart, France.
FUNDING
This research was funded by the Ramsay Health Cooperation Group for Education and Research (GCS Ramsay Health Care, No. COS-RGDS-2018-12-013). Ramsay Health Care supported fees for the radiology technician, for English language editing (by Newmed Publishing Ltd) and for the validation of the statistical analyses pertaining to survival analyses and multivariable statistics (by Horiana Ltd).
AUTHORS’ CONTRIBUTIONS
G.R.: Conceptualization, Methodology, Validation, Investigation, Supervision, Project administration, Funding acquisition, Writing—Original draft, Writing—Review & editing. M.G. and C.L.: Methodology, Validation, Formal analysis, Investigation, Data curation, Visualization, Writing—Review & editing. S.F.: Software, Resources, Data curation. G.B. and E.L-L.: Investigation, Supervision. Y.C.: Conceptualization, Software, Resources, Data curation. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. All authors had access to the study data and approve them for publication. All authors read and approved the final version of the manuscript.
DATA AVAILABILITY STATEMENT
Anonymized data resulting from this study can be made available upon reasonable request. Requests should be directed to rostotom@orange.fr.
CONFLICT OF INTEREST STATEMENT
G.R. reports receiving consultancy fees from Astellas (board on Roxadustat, 2019–2021, 2023), GlaxoSmithKline (board on Daprodustat, 2022-2023), Vifor (board on Difelikefalin, 2021–2023) and reports research funding for scientific presentations from Amgen, Astellas, Baxter, Hemotech, Gambro Hospal, Nipro, Physidia and Theradial. He also reports receiving honoraria from Amgen, Astellas, GlaxoSmithKline, Roche, Sanofi and Vifor. Additionally, he currently serves on Astellas’s and Baxter’s boards of speakers. All co-authors have nothing to disclose, they received no funding for this manuscript. G.R. is employed as nephrologist by the Société d’Exercice Libéral à Responsabilité Limitée (SELARL) (a limited liability company for non-commercial services) de Néphrologie et de Dialyse des Drs Rostoker et Associés, and he is the manager of the SELARL. M.G. and C.L. are employed by the SELARL de Néphrologie et de Dialyse des Drs Rostoker et Associés at the Claude Galien private hospital in Quincy-sous-Sénart. G.B. and E.L-L. are contractors with the SELARL de Néphrologie et de Dialyse des Drs Rostoker et Associés at the Claude Galien private hospital in Quincy-sous-Sénart. S.F. is employed by the Société Civile de Moyens (SCM) Imagerie Claude Galien at the Claude Galien private hospital in Quincy-sous-Sénart. Y.C. is employed by the SCM Imagerie Quincy as radiologist at the Claude Galien private hospital in Quincy-sous-Sénart and he is one of the managers of the SCM. The organization that funded the study had no role in its design, nor in the collection, analyses or interpretation of data, in the writing of the manuscript or in the decision to publish the results.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Anonymized data resulting from this study can be made available upon reasonable request. Requests should be directed to rostotom@orange.fr.