key: cord-0076833-it3u8kb9 authors: Tantisattamo, Ekamol; Imhof, Celine; Jager, Kitty J; Hilbrands, Luuk B; Guidotti, Rebecca; Islam, Mahmud; Katicic, Dajana; Konings, Constantijn; Molenaar, Femke M; Nistor, Ionut; Noordzij, Marlies; Ferrero, María Luisa Rodríguez; Verhoeven, Martine A M; de Vries, Aiko P J; Kalantar-Zadeh, Kamyar; Gansevoort, Ron T; Vart, Priya title: Association of obesity with 3-month mortality in kidney failure patients with COVID-19 date: 2022-03-21 journal: Clin Kidney J DOI: 10.1093/ckj/sfac083 sha: 3ab24c778e509c54efa3ed4dc1abeb5ee40102b6 doc_id: 76833 cord_uid: it3u8kb9 BACKGROUND: In the general population with COVID-19, obesity is associated with an increased risk of mortality. Given the typically observed obesity paradox among patients on kidney function replacement therapy (KFRT), especially dialysis patients, we examined the association of obesity with mortality among dialysis patients or living with a kidney transplant with COVID-19. METHODS: Data from the European Renal Association COVID-19 Database (ERACODA) were used. KFRT-patients diagnosed with COVID-19 between February 1(st), 2020, and January 31(st), 2021 were included. The association of Quetelet's body mass index (BMI) (kg/m(2)), divided into: <18.5 (lean), 18.5-24.9 (normal weight), 25-29.9 (overweight), 30-34.9 (obese I) and ≥35 (obese II/III), with 3-month mortality was investigated using Cox proportional-hazards regression analyses. RESULTS: In 3,160 patients on KFRT (mean age:65 years, male:61%), 99 patients were lean, 1,151 normal weight (reference), 1,160 overweight, 525 obese I, and 225 obese II/III. During follow-up of 3 months, 28%, 20%, 21%, 23%, and 27% of patients died in these categories, respectively. In the fully adjusted model, the HRs for 3-month mortality were 1.65 (95%CI:1.10,2.47), 1 (ref.), 1.07 (95%CI:0.89,1.28), 1.17 (95%CI:0.93,1.46) and 1.71 (95%CI:1.27,2.30), respectively. Results were similar among dialysis patients (N = 2,343) and among those living with a kidney transplant (N = 817) (p(interaction) = 0.99), but differed by sex (p(interaction) = 0.019). In males, the HRs for the association of aforementioned BMI categories with 3-month mortality were 2.07 (95% CI:1.22, 3.52), 1 (Ref.), 0.97 (95% CI: 0.78. 1.21), 0.99 (95% CI: 0.74, 1.33) and 1.22 (95%CI:0.78, 1.91) respectively, and in females corresponding HRs were 1.34 (95% CI: 0.70, 2.57), 1 (Ref.), 1.31 (95% CI: 0.94, 1.85), 1.54 (95% CI: 1.05, 2.26) and 2.49 (95%CI:1.62, 3.84) respectively.”. CONCLUSION: In KFRT-patients with COVID-19, on dialysis or a kidney transplant, obesity is associated with an increased risk of mortality at 3 months. This is in contrast to the obesity paradox generally observed in dialysis patients. Additional studies are required to corroborate the sex difference in the association of obesity with mortality. Obesity is a well-established risk factor for mortality in the general population, such that Quetelet's body mass index (BMI) over 30 kg/m² is associated with a sharp increase in the risk of mortality [1] . However, the relationship between obesity and mortality has not been observed consistently across all population subgroups. Among patients on kidney function replacement therapy (KFRT), especially dialysis patients, obesity is reported to be associated with better survival, a phenomenon known as the 'obesity paradox' [2] . Already early in the COVID-19 pandemic, obesity was identified as a key risk factor for severe complications including death among the general population with COVID-19 [3] . To our knowledge, there has not been a comprehensive study to investigate the association of obesity with the risk of mortality among patients on KFRT with COVID-19, and consequently, it is unclear whether the 'obesity paradox' holds true also among patients on KFRT with COVID-19 infection [4] . Given the high COVID-19 case-fatality rate among patients on KFRT [5] and thereby the The ERACODA database was established in March 2020 and currently involves the cooperation of approximately 220 physicians representing over 140 centers in 33 countries, mostly in Europe. Data was collected on adult (≥18 years) patients with kidney failure, either on dialysis or living with a functioning kidney allograft, who were diagnosed with COVID-19 based on a positive result on a real-time polymerase chain reaction assay or rapid antigen test of nasal and/or pharyngeal swab specimens, and/or compatible findings on CT scan or chest X-ray. Data were voluntarily reported from outpatients and hospitalized patients by physicians responsible for their care [6] . The ERACODA database is hosted at the University Medical Center Groningen, the Netherlands. Data is recorded using REDCap software (Research Electronic Data Capture, Vanderbilt University Medical Center, Nashville, TN, USA) for data collection [7] . Patient information is stored pseudonymized. The study was approved by the Institutional Review Detailed information was collected on patient (age, sex, ethnicity, height, weight, frailty, comorbidities, hospitalization, and medication use) and COVID-19 related characteristics (symptoms, vital signs, and laboratory test results) at presentation. Frailty was assessed using the Clinical Frailty Score developed by Rockwood et al [8] . BMI was calculated by dividing body weight by square of height, expressed in kg/m 2 , and used to assess obesity categorized as per World Health Organization (WHO) classification i.e. <18.5 (underweight), 18.5-24.9 (normal), 25-29.9 (overweight), 30-34.9 (obesity Class I) and ≥35 kg/m 2 (obesity Class II/III) [9] . Obesity classes II and III were merged to allow sufficient patients in this category. The primary outcome of this study was vital status at three months after COVID-19 diagnosis and the secondary outcomes were hospitalization, Intensive Care Unit (ICU) admission and, in-hospital mortality. All patients who presented between February 1 st , 2020 and January 31 st , 2021 and for whom information on BMI, type of KFRT, date of presentation, and threemonth vital status was available, were included in the analysis (Supplementary Figure S1 ). Baseline characteristics are presented for the total population, and by categories of BMI. Characteristics were compared between groups using ANOVA for continuous variables (Kruskal All analyses were performed using Stata version 14.0 (College Station, TX). A 2-sidedvalue less than 0.05 indicated statistical significance. A total of 3,160 patients were analyzed, of which 3% had underweight, 36% normal weight, 37% overweight, 17% obesity class I, and 7% obesity class II/III (Table 1) . When compared to normal weight, the higher obesity categories were characterized by lower age, more women, and higher frailty. Hypertension and diabetes was more prevalent in the obesity categories compared with the normal weight category. Also the prevalence of cough, shortness of breath, and myalgia/arthralgia was higher in the obesity categories compared with the normal weight category, as was the level of C-reactive protein (CRP). Dialysis patients on average were older and had a higher comorbidity burden than those living with a kidney transplant. However, the mean BMI, the prevalence of obesity, and the trends in the distribution of patient demographics, comorbidities, and disease characteristics across BMI categories in dialysis patients and transplant recipients were similar to trends in the total population (Supplementary Tables S1 and S2) . The percentage of patients who experienced 3-month mortality was 28.3%, 20 Figure 2 ). There was no interaction between the type of KFRT (dialysis/kidney transplant) and BMI categories (p for interaction=0.99 in the fully adjusted model). The models that were used demonstrated no violation of the proportional-hazards assumption (p for the difference in fully adjusted model with and without time-varying covariates=0.13 in the total population, 0.21 in dialysis patients, and 0.62 in transplant recipients). The association between BMI and hospitalization rate was not statistically significant in the total study population, nor in dialysis patients or in transplant recipients when analyzed separately Table S5 ). The association between obesity class II/III (vs. normal weight) and 3-month mortality was consistent across all examined subgroups except for sex ( Figure 3 ). In general, KM-curves demonstrated lowest cumulative survival in underweight category among men and in obese class II/III category in women (Supplementary Figure S2 ). Obesity class II/III was significantly associated with 3-month mortality among females but not in males (p for interaction=0.019 in the fully adjusted model) (Figures 3 and 4 ; Table 3 ). The association between BMI (continuous) and mortality indicated a consistent increase in the risk of mortality in patients with BMI >28 kg/m 2 (Supplementary Figure S3 ). Among men, the risk appeared to increase from BMI >28 kg/m 2 and in women from BMI >25 kg/m 2 (Supplementary Figure S3 Table S9 ). Table S10 ). In this large cohort of patients on KFRT with COVID-19, we showed an independent association between obesity and increased risk of mortality. This association was consistent among dialysis patients and those living with a kidney transplant. Interestingly, the association was different among males and females, such that the risk of mortality associated with obesity vs. normal weight was higher in females compared with males. Several previous studies have reported an association between obesity and increased risk of COVID-19 related complications including mortality in the general population with COVID-19 [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] . To our knowledge, the present study is the first to report comprehensively on the obesity-mortality relationship among patients on KFRT with COVID-19. In our study, compared to the WHO defined category of normal weight, obesity class II/III was associated with an increased risk of mortality. Of note, when the association between BMI and mortality was investigated on a continuous scale, the risk of mortality appeared to increase from a BMI over approximately 28 kg/m 2 . An increased mortality risk above a BMI of approximately 28 kg/m 2 has also been observed in a meta-analysis of 28 studies (N=112,682) among the general population with COVID-19 [21] and in a large study (N~6.9 million) investigating the association between BMI and COVID-19 related complications in the general population [22] . These studies in the general population also reported increased mortality risk at low BMI as in our study. Consequently, the results observed in our study are in line with the previous studies in the general population, but in contrast to the often observed 'obesity paradox' among patients on KFRT. Especially obese dialysis patients are at lower long-term non-COVID-19 mortality risk when compared to dialysis patients with normal weight [2] . The reversal of the 'obesity paradox' among patients on KFRT with COVID-19 could be related to several factors. First, the influence of obesity on mortality may differ in acute versus chronic diseases. Patients on KFRT that are in poor physical condition due to an underlying illness often loose weight. Thus, obesity may reflect the absence of debilitating disorders and therefore contribute to better long-term outcomes of chronic conditions, such as cardiovascular diseases [23] . However, COVID-19 is an acute viral illness and causes rapid clinical outcomes. Therefore, the survival advantage associated with obesity among patients on KFRT may not be seen when these patients suffer from COVID-19, as this occurs especially on the long term. Second, intubation, positioning, and movement may be difficult among seriously ill patients with obesity which may complicate patients' recovery from COVID-19 [24] . Men and women exhibited a difference in the BMI-mortality relationship in our study. Previously, a large study (N=502,493) in subjects from the general population with COVID-19, and another study in hospitalized COVID-19 patients, showed similar results regarding COVID-19 related mortality [25, 26] . Also these studies indicated an increase in mortality with increasing obesity in women, but not in men. The exact reason for the observed difference in the BMImortality relationship between men and women is not fully clear to us, though it may be related to sex differences in the anatomy of lungs and abdominal cavity [27, 28] which may cause difficulty in breathing in presence of obesity [1] . It may also be that in a population like ours, 'normal weight' among men is in part a consequence of increased comorbidity burden in men who would have been (slightly) obese if not suffering from comorbidity. Accordingly, when the association between BMI (continuous) and the risk of mortality was investigated for both sex separately, in men the risk of mortality did not appear to be lowest among those with BMI in the 'normal weight' range as this as the case in women. To our knowledge, such a difference in the association of BMI with mortality has not be observed in the general population with COVID-19. Of note, in our study the absolute COVID-19 mortality rate in obese men and women was similar, whereas the absolute COVID-19 mortality rate in the normal-weight category was almost two-fold higher in men compared with women. This questions whether the sex difference in our results should be interpreted as excess relative mortality in obese women when compared to obese men, or more as higher absolute mortality rate in normal weight men when compared to normal weight women. Putting more emphasis on this latter finding is supported by the fact that there are far more people with normal weight in our cohort (N=1,160) than with obesity class II/III (N=225). Future studies are required to better understand the reasons for the observed sex difference in the BMI-mortality relationship in our study. The most important strength of our study is that it reports on a large dataset with detailed information on patients' demographics, comorbidities, reasons for COVID-19 testing, disease characteristics including symptoms, and laboratory test results. This allowed accounting for known confounders in the BMI-mortality relationship and examination of results across key clinical subgroups, thereby allowing a comprehensive assessment of the BMI-mortality relationship among patients on KFRT with COVID-19. However, this study also has limitations. First, patients who presented with COVID-19 may not be representative of the overall population of KFRT patients with COVID-19 which may limit the generalizability of our findings. However, it is worth noting that case-fatality rates observed in our study are comparable to those reported in other studies from patients on KFRT with COVID-19 [4, [29] [30] [31] [32] [33] . Second, a significant proportion of patients (18.1%) had missing information on BMI. These patients were predominantly Caucasian males and were less likely to have comorbidities than patients in the cohort with information on BMI (Table S7 ). In a sensitivity analysis that included these patients after multiple imputations, we found no difference in the observed associations compared with our main findings. Third, because BMI is associated with disease severity and patients with severe symptoms were more likely to be tested for COVID-19, especially early in the COVIDpandemic, there may be a possibility of collider bias [34] . Importantly, we had information on the reason for COVID-19 testing. No heterogeneity was observed in the association between obesity and mortality when patients who were identified through routine screening and those who were identified because of symptoms were analyzed separately, suggesting that this type of bias has no major role. In conclusion, this study shows that among patients on KFRT with COVID-19, dialysis patients as well as transplant recipients, obesity is associated with an increased risk of mortality. This is in contrast to the obesity paradox generally observed in dialysis patients. The association of obesity with COVID-19 mortality may be different in men and women, which requires further study, including investigation of potential reasons for this difference. All authors contributed to data collection, study design, data analysis, interpretation, and drafting of this paper. The ERACODA collaboration is an initiative to study prognosis and risk factors for mortality due to COVID-19 in patients with a kidney transplant or on dialysis that is endorsed by the European Renal Association ( Body-mass index and allcause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents Reverse epidemiology of cardiovascular risk factors in maintenance dialysis patients Factors associated with COVID-19-related death using OpenSAFELY COVID-19-related mortality in kidney transplant and dialysis patients: results of the ERACODA collaboration CKD is a key risk factor for COVID-19 mortality ERACODA: the European database collecting clinical information of patients on kidney replacement therapy with COVID-19 The REDCap consortium: Building an international community of software platform partners A global clinical measure of fitness and frailty in elderly people World Health Organization. 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