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American Journal of Kidney Diseases

CKD Progression and Mortality Among Men and Women: A Nationwide Study in Sweden

  • Oskar Swartling
    Correspondence
    Address for Correspondence: Oskar Swartling, MD, Department of Medicine Solna, Karolinska Institutet, Clinical Epidemiology Division T2, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
    Affiliations
    Department of Medicine, Clinical Epidemiology Division, Karolinska Institutet, Stockholm, Sweden
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  • Helena Rydell
    Affiliations
    Renal unit, Department of Clinical Sciences, Interventions and Technology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden

    Swedish Renal Registry, Department of Internal Medicine, Ryhov Regional Hospital, Jönköping, Sweden
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  • Maria Stendahl
    Affiliations
    Swedish Renal Registry, Department of Internal Medicine, Ryhov Regional Hospital, Jönköping, Sweden
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  • Mårten Segelmark
    Affiliations
    Swedish Renal Registry, Department of Internal Medicine, Ryhov Regional Hospital, Jönköping, Sweden

    Department of Clinical Sciences, Division of Nephrology, Lund University and Skane University Hospital, Lund, Sweden
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  • Ylva Trolle Lagerros
    Affiliations
    Department of Medicine, Clinical Epidemiology Division, Karolinska Institutet, Stockholm, Sweden

    Center for Obesity, Academic Specialist Center, Stockholm Health Services, Stockholm, Sweden
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  • Marie Evans
    Affiliations
    Renal unit, Department of Clinical Sciences, Interventions and Technology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden

    Swedish Renal Registry, Department of Internal Medicine, Ryhov Regional Hospital, Jönköping, Sweden
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Open AccessPublished:January 09, 2021DOI:https://doi.org/10.1053/j.ajkd.2020.11.026

      Rationale & Objective

      Chronic kidney disease (CKD) is a global health problem with increasing prevalence. Several sex-specific differences have been reported for disease progression and mortality. Selection and survival bias might have influenced the results of previous cohort studies. The objective of this study was to investigate sex-specific differences of CKD progression and mortality among patients with CKD not receiving maintenance dialysis.

      Study Design

      Observational cohort study.

      Setting & Participants

      Adult patients with incident CKD glomerular filtration rate categories 3b to 5 (G3b-G5) identified between 2010 and 2018 within the nationwide Swedish Renal Registry-CKD (SRR-CKD).

      Exposure

      Sex.

      Outcomes

      Time to CKD progression (defined as a change of at least 1 CKD stage or initiation of kidney replacement therapy [KRT]) or death. Repeated assessments of estimated glomerular filtration rate (eGFR).

      Analytical Approach

      CKD progression and mortality before KRT were assessed by the cumulative incidence function methods and Fine and Gray models, with death handled as a competing event. Sex differences in eGFR slope were estimated using mixed effects linear regression models.

      Results

      7,388 patients with incident CKD G3b, 18,282 with incident CKD G4, and 9,410 with incident CKD G5 were identified. Overall, 19.6 (95% CI, 19.2-20.0) patients per 100 patient-years progressed, and 10.1 (95% CI, 9.9-10.3) patients per 100 person-years died. Women had a lower risk of CKD progression (subhazard ratio [SHR], 0.88 [95% CI, 0.85-0.92]), and a lower all-cause (SHR, 0.90 [95% CI, 0.85-0.94]) and cardiovascular (SHR, 0.83 [95% CI, 0.76-0.90]) mortality risk. Risk factors related to a steeper decline in eGFR included age, sex, albuminuria, and type of primary kidney disease.

      Limitations

      Incomplete data for outpatient visits and laboratory measurements and regional differences in reporting.

      Conclusions

      Compared to women, men had a higher rate of all-cause and cardiovascular mortality, an increased risk of CKD progression, and a steeper decline in eGFR.

      Graphical abstract

      Index Words

      Women are overrepresented in the early chronic kidney disease (CKD) population. Recent evidence has found sex-specific differences in CKD progression and mortality. However, those studies have mostly been general population cohorts or smaller risk cohorts. The present study used a national CKD registry in Sweden that included all nephrology outpatient visits from 2008 to 2018 with CKD stages 3b-5. Women were found to be less likely to progress by 1 CKD stage or start kidney replacement therapy and had a slower loss of eGFR per year, with differences also in primary renal diagnoses. In addition, women overall had lower all-cause and cardiovascular mortality. Understanding sex differences in CKD outcomes are central for kidney disease planning and prevention.
      Editorial, p. 177
      Chronic kidney disease (CKD) is a common condition with an estimated prevalence of 10.6%-13.4%.
      • Hill N.R.
      • Fatoba S.T.
      • Oke J.L.
      • et al.
      Global prevalence of chronic kidney disease – a systematic review and meta-analysis.
      The prevalence has risen during the last decades, mainly because of the increase in diabetes mellitus and cardiovascular disease and an ageing population.
      • Hill N.R.
      • Fatoba S.T.
      • Oke J.L.
      • et al.
      Global prevalence of chronic kidney disease – a systematic review and meta-analysis.
      Collaborators GdaH
      Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015.
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      • Fraser S.D.S.
      The ascending rank of chronic kidney disease in the global burden of disease study.
      It has been projected that the number of people receiving kidney replacement therapy (KRT) will have doubled in 10 years.
      • Liyanage T.
      • Ninomiya T.
      • Jha V.
      • et al.
      Worldwide access to treatment for end-stage kidney disease: a systematic review.
      Although early-stage CKD is common in the population, the proportion of patients progressing to later stages is relatively low.
      • Eriksen B.O.
      • Ingebretsen O.C.
      The progression of chronic kidney disease: a 10-year population-based study of the effects of gender and age.
      However, comorbidity and mortality in later stages of CKD is substantial. Knowledge of factors influencing the transition between different CKD stages and progression of CKD is insufficient.
      There are unexplained sex-specific disparities regarding incidence, prevalence, and mortality in different CKD stages and progression to KRT initiation. The prevalence of early CKD is higher in women than in men.
      • Hill N.R.
      • Fatoba S.T.
      • Oke J.L.
      • et al.
      Global prevalence of chronic kidney disease – a systematic review and meta-analysis.
      ,
      • Carrero J.J.
      • Hecking M.
      • Chesnaye N.C.
      • Jager K.J.
      Sex and gender disparities in the epidemiology and outcomes of chronic kidney disease.
      • Murphy D.
      • McCulloch C.E.
      • Lin F.
      • et al.
      Trends in prevalence of chronic kidney disease in the United States.
      • Bikbov B.
      • Perico N.
      • Remuzzi G.
      on behalf of the GBD Genitourinary Diseases Expert Group. Disparities in chronic kidney disease prevalence among males and females in 195 countries: analysis of the Global Burden of Disease 2016 study.
      However, many studies,
      • Antlanger M.
      • Noordzij M.
      • van de Luijtgaarden M.
      • et al.
      Sex differences in kidney replacement therapy initiation and maintenance.
      • Neugarten J.
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      Effect of gender on the progression of nondiabetic renal disease: a meta-analysis.
      • Turin T.C.
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      Lifetime risk of ESRD.
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      • Pippias M.
      • Stel V.S.
      • et al.
      Lifetime risk of renal replacement therapy in Europe: a population-based study using data from the ERA-EDTA Registry.
      but not all,
      • Jafar T.H.
      • Schmid C.H.
      • Stark P.C.
      • et al.
      The rate of progression of renal disease may not be slower in women compared with men: a patient-level meta-analysis.
      ,
      • Nitsch D.
      • Grams M.
      • Sang Y.
      • et al.
      Associations of estimated glomerular filtration rate and albuminuria with mortality and renal failure by sex: a meta-analysis.
      suggest a higher risk of KRT in men. Suggested explanations include a faster progression of CKD in men,
      • Halbesma N.
      • Brantsma A.H.
      • Bakker S.J.
      • et al.
      Gender differences in predictors of the decline of renal function in the general population.
      unequal access to KRT,
      • Sparke C.
      • Moon L.
      • Green F.
      • et al.
      Estimating the total incidence of kidney failure in Australia including individuals who are not treated by dialysis or transplantation.
      and increased mortality in non-KRT CKD glomerular filtration rate category 5 (G5) among women. Minutolo et al
      • Minutolo R.
      • Gabbai F.B.
      • Chiodini P.
      • et al.
      Sex differences in the progression of CKD among older patients: pooled analysis of 4 cohort studies.
      recently investigated the effect of sex on the progression of CKD in a multicohort study group of 2,335 patients with moderate to advanced CKD. They reported a 50% higher risk of progression to KRT in men than in women across all CKD stages. The same pattern was seen using slope analysis of loss of estimated glomerular filtration rate (eGFR) per year. Whether these results from patients included in 4 regional Italian cohorts are generalizable to unselected nephrology patients remains to be seen. The biological mechanisms for the faster decline of eGFR seen in men is not known. Several theories have been suggested, such as sex-specific differences in oxidative stress, metabolism of nitrogen oxide, and the actions of sex steroids.
      • Carrero J.J.
      • Hecking M.
      • Chesnaye N.C.
      • Jager K.J.
      Sex and gender disparities in the epidemiology and outcomes of chronic kidney disease.
      The present study investigated the association between sex and progression of CKD and mortality in moderate- to advanced-stage CKD in a nationwide, population-based inception registry of patients with CKD G3b-G5. This study presents the results from the initial 10 years of the Swedish Renal Registry–-Chronic Kidney Disease (SRR-CKD).

      Methods

      Study Population

      SRR-CKD is a national registry including patients with CKD who are not receiving dialysis. Patients are included in the registry if they have CKD according to KDIGO (Kidney Disease: Improving Global Outcomes) criteria
      Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group
      KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
      and have been referred to a nephrology outpatient clinic.
      According to the inclusion criteria, a patient should be registered when eGFR is below 30 mL/min/1.73 m2 (CKD G4) and followed thereafter. Centers are also allowed to include patients at first eGFR of 30 to <45 mL/min/1.73 m2 (CKD G3b) as long as the centers are consistent with their inclusion limits. The number of nephrology outpatient clinics reporting to the registry corresponds to a coverage of 98%. One outpatient visit per year is mandatory to report, but clinics are encouraged to enter all visits. Visits are entered manually by the treating clinic in a Web-based database interlinked with the Swedish Renal Registry for dialysis and transplantation. Patients receive oral and written information about the SRR the first time they are entered and have the possibility to refuse participation or opt out at any time. Under Swedish law, written consent is not required because the registry constitutes quality control, a fundamental part of public health care.
      The present study included patients >18 years of age who had their first registration in SRR-CKD from January 1, 2010, through November 8, 2018, and an eGFR below 45 mL/min/1.73 m2. Because the registry started in 2008 and at that point included the prevalent outpatient population, it was decided this study would exclude those who were included before 2010 to form an inception cohort. Patients who had already started dialysis or who had received a kidney transplant were excluded. The study was approved by the regional ethics board in Stockholm.

      Exposure and Measures

      This study used sex as the primary exposure of interest. This was registered in all participants upon inclusion. The primary kidney diagnosis was assigned by the treating nephrologist according to the European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) coding system. Diagnoses were based on clinical criteria (ie, most glomerular and proteinuria diseases were based on kidney biopsy). Comorbidities (presence of diabetes mellitus, ischemic heart disease, peripheral arterial disease, cerebrovascular disease, other heart diseases including congestive heart failure, and malignancies) were entered at baseline. At each outpatient visit, blood pressure and laboratory data (serum creatinine, hemoglobin, albumin, phosphate, calcium, parathyroid hormone, and C-reactive protein, as well as urinary albumin-creatinine ratio) are mandatory, whereas other laboratory tests and anthropometric data are optional. Type of antihypertensive medication and erythropoietin-stimulating agents, including dosage, were also entered. Other treatments (vitamin D, calcimimetics, lipid-lowering drugs, and phosphate binders) were added as yes or no, except for iron supplementation, where route of administration (oral or intravenous) must be specified.

      Outcomes and Effect Modification

      Our primary outcomes were time to CKD progression, time to death before KRT, and eGFR slope during follow-up. The secondary outcome was time to cardiovascular death before KRT. The event termed CKD progression was defined as suggested by KDIGO as a drop to a more severe CKD stage, or initiation of KRT
      Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group
      KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
      . Information on KRT was obtained through direct linkage within the SRR. The eGFR slope was estimated from repeated assessments of eGFR using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation
      • Levey A.S.
      • Stevens L.A.
      • Schmid C.H.
      • et al.
      A new equation to estimate glomerular filtration rate.
      during the nondialysis follow-up, from first inclusion to either death, start of KRT, or end of follow-up (referral back to primary health care or November 8, 2018), whichever came first. The date and cause of death (ERA-EDTA classification system) were obtained from the SRR. eGFR is entered into the registry by the local clinics on an ongoing basis. The SRR is once yearly linked to the national cause of death register to update with any missing information. Thus, if a patient was referred back to primary health care, we were still able to collect information on mortality and KRT initiation. We further studied whether CKD stage was an effect modifier of the association between sex and CKD progression (at baseline) and mortality (time-dependent).
      In our analyses of time to CKD progression, we followed the patients from baseline until the date when the patient dropped by 1 CKD stage or started KRT (event), or death (competing event) or end of follow-up (censoring). We further investigated the risk of CKD stage-specific progression, where the follow-up time was from the first date in each CKD stage. When computing the eGFR slope, all eGFR assessments were used until end of follow-up, start of KRT, or death. The time to all-cause mortality before KRT was analyzed from baseline until death (event), start of KRT (competing event), or end of follow-up (censoring). In the analysis of time to cardiovascular mortality we regarded noncardiovascular mortality as a competing risk. Missing cause of death was treated as death from unknown cause. To account for a potential difference in CKD progression between post- and premenopausal women, we also performed a subgroup analysis, stratifying on the mean menopausal age in Sweden.

      Statistical Analysis

      Descriptive statistics for continuous variables were calculated using mean ± SD or median and interquartile range (IQR). For categorical variables, the proportion was used. Albuminuria was categorized according to the KDIGO classification system, where A1 corresponds to urinary albumin-creatinine ratio <3 mg/mmol; A2, 3-30 mg/mmol; and A3, >30 mg/mmol.
      Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group
      KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
      Patients were divided into CKD categories G3b-G5. Incident CKD stage corresponded to the first visit registered in every CKD stage (time-varying). Once a patient had progressed to a more severe CKD stage, any later improvements were disregarded.
      Risk factors for progression were graphically visualized by sex and both static and time-varying CKD stages through the cumulative incidence function method, accounting for the competing event. Differences were assessed using the Wald test. Fine and Gray models were fitted for time to progression overall and by baseline CKD stage, adjusting for variables a priori known to be associated with CKD progression (age, sex, primary kidney disease; first CKD stage, or first eGFR in a given CKD stage; diabetes, history of cardiovascular disease, and systolic blood pressure). We further studied the interaction between sex and baseline CKD stage, and we stratified by CKD stage at baseline. Risk factors for all-cause mortality before KRT were graphically visualized by sex and time-varying CKD stage through the cumulative incidence function method, accounting for the competing event (KRT). We fitted Fine and Gray models for time to death before KRT, with CKD stage as a time-varying covariate, adjusting for the above-mentioned confounders. For cardiovascular mortality before KRT, cumulative incident plots by sex and time-varying CKD stage were used. Fine and Gray models were fitted for time to cardiovascular death before KRT and by time-varying CKD stage, adjusting for the same set of confounders. We further studied the interaction between CKD stage and sex, stratifying the models according to CKD stage. Differences in eGFR slope (expressed as eGFR change in mL/min/1.73 m2 per year) were assessed by linear mixed effects models with random intercept and slope in separate regression models including an interaction term between the variable of interest and time. Differences between annual slope in men and that in women were studied, also adjusting for CKD stage at baseline. In accordance with our progression analyses, we whether there was any interaction between CKD stage at baseline and sex. All analyses were based on complete case records. Due to a relatively large number of missing values for the nonmandatory variable albuminuria, additional adjustments for this were added as a secondary analysis. Analyses were performed using Stata version 15 software (StataCorp).

      Results

      Patient Characteristics

      In total, 31,611 patients were included in the SRR-CKD between 2008 and 2018. We excluded 5,121 patients who were included before January 1, 2010, 18 who were younger than 18 years of age, and 193 who had already been on KRT before entering the SRR-CKD (Fig S1). The remaining 26,279 patients were included in our analyses. The mean   number of visits during follow-up was 4.5 (SD: 4.1; IQR, 2-6) and was similar between men and women. There were 7,388 patients included who at their first visit had CKD G3b, whereas 18,282 and 9,410 either started with or progressed to CKD G4 and G5, respectively. The characteristics of the patients at baseline by sex and first visit in each CKD stage are shown in Table 1. Men were more represented in all CKD stages (68.2% in G3b, 63.6% in G4, and 62.5% in G5), but there were no differences by sex in eGFR by sex at first visit in each CKD stage.
      Table 1Baseline Characteristics by Sex at First Visit in Each CKD Stage
      CKD G3b (n = 7,388)CKD G4 (n = 18,282)CKD G5 (n = 9,410)
      MenWomenMenWomenMenWomen
      No. of patients5,042 (68.2%)2,346 (31.8%)11,620 (63.6%)6,662 (36.4%)5,844 (62.5%)3,526 (37.5%)
      Age, y71.0 [62.7-77.3]69.7 [60.5-76.8]73.1 [64.4-80.0]73.5 [64.5-80.3]71.1 [61.0-79.4]71.7 [60.7-79.8]
      Progression from earlier stageNANA2,194 (18.9%)965 (14.5%)3,664 (62.3%)1,978 (56.1%)
      Body mass index, kg/m228.7 ± 5.628.6 ± 6.828.1 ± 5.428.8 ± 6.627.7 ± 5.428.0 ± 6.6
      Blood pressure, mm Hg
        Systolic137 ± 21136 ± 21139 ± 21139 ± 22142 ± 22142 ± 23
        Diastolic77 ± 1277 ± 1277 ± 1276 ± 1278 ± 1276 ± 13
      Primary kidney disease
       Diabetic kidney disease1,076 (21.3%)375 (16.0%)2,721 (23.4%)1,321 (19.8%)1,404 (23.9%)827 (23.4%)
       Glomerulonephritis474 (9.4%)202 (8.6%)981 (8.4%)466 (7.0%)663 (11.3%)283 (8.0%)
       Hypertensive/renovascular nephropathy1,439 (28.6%)603 (25.7%)3,447 (29.7%)1,905 (28.6%)1,550 (26.3%)810 (23.0%)
       Hereditary diseases184 (3.7%)133 (5.7%)460 (4.0%)345 (5.2%)341 (5.8%)291 (8.3%)
       Uremia unknown859 (17.0%)490 (20.9%)1,516 (13.0%)993 (14.9%)670 (11.4%)453 (12.8%)
       Other specified causes1,007 (20.0%)543 (23.1%)2,492 (21.5%)1,632 (24.5%)1,256 (21.3%)861 (24.4%)
      Comorbidity
       Diabetes mellitus1,846 (36.6%)702 (29.9%)4,211 (36.2%)2,231 (33.5%)1,924 (32.7%)1,186 (33.6%)
       Ischemic heart disease965 (19.1%)284 (12.1%)2,376 (20.5%)1,004 (15.1%)859 (14.6%)420 (11.9%)
       CHF/other heart disease951 (18.9%)298 (12.7%)2,095 (18.0%)1,048 (15.7%)706 (12.0%)408 (11.6%)
       PVD293 (5.8%)93 (4.0%)741 (6.4%)305 (4.6%)281 (4.8%)131 (3.7%)
       Malignancies except skin cancer592 (11.7%)176 (7.5%)1,463 (12.6%)620 (9.3%)592 (10.1%)296 (8.4%)
       CBVD401 (8.0%)145 (6.2%)957 (8.2%)422 (6.3%)393 (6.7%)216 (6.1%)
      eGFR, mL/min/1.73 m236.1 ± 4.335.6 ± 4.323.7 ± 4.223.2 ± 4.212.2 ± 2.412.1 ± 2.4
      Creatinine, mg/dL1.89 ± 0.221.52 ± 0.182.69 ± 0.472.16 ± 0.384.81 ± 1.283.83 ± 1.15
      CRP, mg/L5.0 [2.0-8.0]5.0 [2.0-8.0]5.0 [2.0-10.0]5.0 [2.0-9.1]5.0 [2.2-12.0]5.0 [2.5-12.0]
      Albumin, g/dL3.7 ±0.53.6 ± 0.53.7 ± 0.53.7 ± 0.53.5 ± 0.53.5 ± 0.5
      Calcium, mg/dL9.3 ± 0.69.4 ± 0.59.2 ± 0.69.3 ± 0.68.9 ± 0.59.2 ± 0.8
      Phosphate, mg/dL3.4 ± 0.73.7 ± 0.63.8 ± 0.84.0 ± 0.74.9 ± 1.24.8 ± 1.1
      PTH, pg/mL90.6 [62.8-134.0]88.7 [59.4-141.5]125.5 [84.0-189.6]122.6 [79.2-188.7]215.1 [132.1-326.4]201.0 [122.6-321.7]
      Hemoglobin, g/dL13.0 ± 1.712.3 ± 1.412.4 ± 1.711.8 ± 1.411.5 ± 1.511.2 ± 1.4
      Potassium, mEq/L4.3 ± 0.54.2 ± 0.54.5 ± 0.54.4 ± 0.54.5 ± 0.64.4 ± 0.6
      UACR, mg/mmol18.7 [3.7-93.6]8.6 [2.1-66.0]38.0 [7.55-146.0]18.0 [3.7-100.0]121.6 [33.45-263.5]79.0 [15.7-246.7]
      Urea, mg/dL33.6 [27.7-41.5]31.4 [25.8-38.9]45.7 [37.3-57.1]44.0 [35.0-55.7]63.9 [53.2-77.3]61.6 [50.1-74.8]
      Standard bicarbonate, mEq/L23.1 ± 2.723.5 ± 3.022.6 ± 3.223.2 ± 3.421.9 ± 3.322.3 ± 3.4
      Medications
       ESAs629 (13.2%)314 (14.3%)1,904 (17.8%)1,226 (20.0%)2,028 (37.4%)1,378 (42.5%)
       Iron supplements
      Intravenous97 (1.9%)72 (3.1%)472 (4.1%)373 (5.6%)522 (8,9%)402 (11.4%)
      Oral355 (7.0%)213 (9.1%)1,062 (9.1%)732 (11.0%)728 (12.4%)532 (15.1%)
       Antihypertensive
      Excluding diuretics.
      4,285 (85.0%)1,830 (78.0%)9,825 (84.6%)5,529 (83.0%)5,046 (85.8%)2,941 (83.4%)
       No. of antihypertensives
      Excluding diuretics.
      11,140 (22.6%)516 (22.0%)2,507 (21.6%)1,640 (24.6%)1,114 (18.9%)782 (22.2%)
      21,718 (34.1%)754 (32.1%)3,780 (32.5%)2,265 (34.0%)1,786 (30.4%)1,149 (32.6%)
      31,061 (21.0%)375 (16.0%)2,574 (22.2%)1,336 (20.1%)1,471 (25.0%)773 (21.9%)
      4 or more366 (7.3%)74 (3.2%)964 (8.3%)288 (4.3%)675 (11,5%)237 (6.7%)
       Diuretics2,742 (58.0%)1,190 (54.6%)6,903 (65.0%)4,025 (66.1%)3,853 (71.7%)2,288 (72.0%)
       ACEI or ARB2,535 (53.2%)1,023 (46.6%)5,624 (52.5%)3,029 (49.4%)2,676 (49.3%)1,474 (45.4%)
       β-blocker2,140 (44.9%)822 (37.5%)5,463 (51.0%)3,007 (49.0%)3,288 (60.6%)1,918 (59.1%)
       Calcium antagonist1,749 (36.7%)661 (30.1%)4,744 (44.3%)2,417 (39.4%)3,379 (62.3%)1,778 (54.8%)
       Phosphate binder417 (8.7%)350 (16.0%)1,702 (15.9%)1,314 (21.4%)2,322 (42.8%)1,354 (41.7%)
       Vitamin D
      Active + nutritional.
      1,423 (29.8%)793 (36.1%)4,694 (43.8%)2,885 (47.0%)3,679 (67.8%)2,164 (66.7%)
       Calcimimetics27 (0.6%)30 (1.4%)102 (1.0%)110 (1.8%)134 (2.5%)123 (3.8%)
       Statin2,760 (57.9%)1,003 (45.7%)6,073 (56.7%)3,062 (49.9%)2,940 (54.2%)1,575 (48.6%)
      Patients may appear in multiple CKD stages, depending on progression. Characteristics are at baseline for patients who started at the given stage or at first visit for patients who progressed to the listed stage. Values for continuous data given as mean ± SD or median [IQR]; for categorical data, as count (%). Conversion factors: creatinine in mg/dL to μmol/L, ×88.4; calcium in mg/dL to mmol/L, ×0.2495; phosphate in mg/dL to mmol/L, ×0.3229; and urea in mg/dL to mmol/L, ×0.357.
      Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CBVD, cerebrovascular disease; CHF, congestive heart failure; CKD, chronic kidney disease; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; ESA, erythropoeitin-stimulating agent; G3b/4/5, glomerular filtration categories 3b, 4, and 5; IQR, interquartile range; PTH, parathyroid hormone; PVD, peripheral vascular disease.
      a Excluding diuretics.
      b Active + nutritional.

      Progression of CKD

      Figure 1 illustrates the unadjusted cumulative incidence function curve of CKD progression (ie, transition to worse CKD stage or start of KRT) for men and women overall and by respective time-varying CKD stage. Overall, there were 19.6 (95% CI, 19.2-20.0) patients per 100 person-years who had a CKD progression event. For men and women, the rates of CKD progression were 20.8 (95% CI, 20.3-21.3) and 17.6 (95% CI, 17.1-18.2) patients per 100 person-years, respectively. The stage-specific progression for women was 21.3 (95% CI, 20.0-22.7), 13.8 (95% CI, 13.2-14.4), and 28.6 (95% CI, 27.3-30.1) patients per 100 person-years in CKD G3, G4, and G5, respectively. In men, the incidence of CKD progression was 22.8 (95% CI, 21.9-23.7), 16.4 (95% CI, 15.9-17.0), and 39.8 (95% CI, 38.4-41.2) patients per 100 person-years in CKD G3, G4, and G5, respectively.
      Figure thumbnail gr1
      Figure 1Cumulative incidence of progression by 1 chronic kidney disease stage or start in kidney replacement therapy for men and women. Abbreviation: CKD G3b-5, glomerular filtration rate categories 3b to G5.
      The risk factors for CKD progression and the corresponding eGFR slopes are presented in Table 2. Overall, men had a higher risk of progression than women. Consequently, the multivariate-adjusted eGFR slope was 0.18 (95% CI, 0.1-0.2) mL/min/1.73 m2 per year slower in women than in men. In the analyses of CKD progression in different CKD stages at baseline, men and women had similar risk of progression in CKD G3b, but women had a lower risk in CKD G4-G5 (Table S1). Results were similar in time-varying analyses of CKD stages (Fig 1, Table S2). In an analysis of baseline CKD and primary kidney disease diagnoses, it was found that, compared to glomerulonephritis, the adjusted risk of CKD progression was higher in patients with diabetic kidney disease but lower in patients with nephrosclerosis or tubulointerstitial nephritis (Table 2). Age, sex, albuminuria, and type of primary kidney disease were risk factors for progression. In the secondary analyses adjusting for level of albuminuria, there were no differences between risk of CKD progression in men and that in women, but women still had 0.19 (95% CI, 0.1-0.3) mL/min/1.73 m2 slower decline in eGFR per year (Table S3). In a secondary analysis in which we focused on the mean menopausal age for women in Sweden (52 years), we found no evidence of smaller differences in eGFR slope between men and women after mean menopausal age. Women progressed 0.57 (95% CI, 0.13-1.02) mL/min/1.73 m2 per year slower than men before 52 years of age and 0.68 (95% CI, 0.57-0.79) mL/min/1.73 m2 per year slower than men after that.
      Table 2Risk for CKD Progression and eGFR Slope
      SHR for CKD Progression (by 1 Stage or KRT Start)Difference in eGFR Slope, mL/min/1.73 m2 per year
      UnadjustedAdjusted
      Adjusted for CKD stage at inclusion, age, sex, primary kidney disease (missing n=5), systolic blood pressure (missing n=1,718), diabetes mellitus, and cardiovascular disease. A total of 63 participants were not included in the analyses due to out-referral/KRT start/end of follow-up at inclusion. Values are based on mean 4.5 measurements for unadjusted and 4.4 measurements for adjusted.
      ,
      Complete cases (n=24,495 [93.2%]). The estimates for albuminuria (missing 12,922 participants) were restricted to those with recorded albuminuria at baseline (n = 13,354).
      UnadjustedAdjusted
      Excluding diuretics.
      ,
      Complete cases (n=24,495 [93.2%]). The estimates for albuminuria (missing 12,922 participants) were restricted to those with recorded albuminuria at baseline (n = 13,354).
      Age
       <55 y  1.00 (reference)1.00 (reference)(reference)(reference)
       55-64 y0.72 (0.67 to 0.76)0.70 (0.65 to 0.74)1.67 (1.3 to 2.1)1.45 (1.3 to 1.6)
       65-70 y0.58 (0.55 to 0.62)0.61 (0.57 to 0.65)1.95 (1.5 to 2.4)1.96 (1.8 to 2.2)
       70-75 y0.51 (0.48 to 0.54)0.54 (0.50 to 0.58)2.09 (1.7 to 2.5)2.19 (2.0 to 2.4)
       75-80 y0.43 (0.40 to 0.46)0.49 (0.45 to 0.51)2.20 (1.8 to 2.6)2.31 (2.1 to 2.5)
       >80 y0.31 (0.29 to 0.33)0.36 (0.33 to 0.39)2.51 (2.1 to 2.9)2.46 (2.3 to 2.6)
      P for linear trend<0.001<0.001<0.001<0.001
      Female sex0.88 (0.85 to 0.92)0.88 (0.85 to 0.92)0.67 (0.6 to 0.8)0.18 (0.1 to 0.2)
      Kidney disease diagnosis
       Glomerulonephritis1.00 (reference)1.00 (reference)(reference)(reference)
       Nephrosclerosis0.56 (0.52 to 0.60)0.78 (0.72 to 0.84)1.37 (1.2 to 1.6)0.36 (0.3 to 0.5)
       Diabetic kidney disease1.30 (1.19 to 1.41)1.30 (1.19 to 1.41)−1.26 (−1.5 to −1.0)−0.63 (−0.8 to −0.5)
       Tubulointerstitial nephritis0.54 (0.50 to 0.58)0.69 (0.64 to 0.75)1.61 (1.4 to 1.8)0.49 (0.4 to 0.6)
       Hereditary diseases0.89 (0.83 to 0.95)1.08 (0.98 to 1.19)−0.03 (−0.2 to 0.2)0.01 (−0.1 to 0.1)
       Undefined0.47 (0.43 to 0.51)0.65 (0.59 to 0.71)1.62 (1.4 to 1.8)0.53 (0.4 to 0.6)
      Albuminuria
       <3 mg/mmol1.00 (reference)1.00 (reference)(reference)(reference)
       3-30 mg/mmol1.38 (1.24 to 1.53)1.32 (1.19 to 1.47)−0.80 (−1.0 to −0.6)−0.33 (−0.4 to −0.2)
       >30 mg/mmol3.18 (2.89 to 3.49)2.79 (2.52 to 3.09)−3.16 (−3.4 to −3.0)−1.10 (−1.2 to −1.0)
      Values in parentheses are 95% CI. Abbreviations: CKD, chronic kidney disease; KRT, kidney replacement therapy; SHR, subhazard ratio.
      a Adjusted for CKD stage at inclusion, age, sex, primary kidney disease (missing n = 5), systolic blood pressure (missing n = 1,718), diabetes mellitus, and cardiovascular disease. A total of 63 participants were not included in the analyses due to out-referral/KRT start/end of follow-up at inclusion. Values are based on mean 4.5 measurements for unadjusted and 4.4 measurements for adjusted.
      b Complete cases (n = 24,495 [93.2%]). The estimates for albuminuria (missing 12,922 participants) were restricted to those with recorded albuminuria at baseline (n = 13,354).

      Mortality

      Overall, the mortality rate was 10.1 (95% CI, 9.9-10.3) per 100 patient-years in the population. Women had a lower mortality rate than men (9.2 [95% CI, 8.8-9.6] vs 10.6 [95% CI, 10.3-11.0] per 100 person-years, respectively) (Table 3). Both men and women had a higher risk of death in more advanced CKD stages. The cumulative incidence of all-cause mortality before KRT was lower for women in all CKD stages except G5 (Fig 2). The adjusted Fine and Gray model showed that women overall were 10% less likely to die (subhazard ratio [SHR], 0.90 [95% CI, 0.85-0.94]) than men (Table 3). Cardiovascular diseases were the most common causes of death in both sexes and across all CKD stages (Table S4). The cardiovascular mortality rate was 3.79 (95% CI, 3.65-3.94) per 100 person-years. The risk of cardiovascular death was lower for women (overall SHR, 0.83 [95% CI, 0.76-0.90]) compared to that in men (Fig 3) but different across CKD G3b-G5 (Table S5, Fig S2).
      Table 3All-Cause Mortality Before KRT According to CKD Stage for Women and Men
      Incidence Rates of All-Cause Mortality Before KRT per 100 Person-YearsAll-Cause Mortality Before KRT, Adjusted SHR, Women vs Men
      Adjusted for age, primary kidney disease, systolic blood pressure, diabetes, cardiovascular disease and other heart disease including heart failure.
      WomenMen
      Overall9.2 (8.8-9.6)10.6 (10.3-11.0)0.90 (0.85-0.94)
      G3b4.6 (4.1-5.3)5.8 (5.4-6.3)0.87 (0.75-1.02)
      G48.0 (7.6-8.5)10.2 (9.8-10.6)0.82 (0.77-0.88)
      G516.4 (15.4-17.5)18.4 (17.4-19.4)1.02 (0.94-1.12)
      Time-varying CKD stage is shown. Values in parentheses are 95% CI. Abbreviations: CKD, chronic kidney disease; G, glomerular filtration rate category; KRT, kidney replacement therapy.
      a Adjusted for age, primary kidney disease, systolic blood pressure, diabetes, cardiovascular disease and other heart disease including heart failure.
      Figure thumbnail gr2
      Figure 2Cumulative incidence of all-cause mortality, by sex and chronic kidney disease stage. Abbreviation: G3b-5, glomerular filtration rate categories 3b to G5.
      Figure thumbnail gr3
      Figure 3Cumulative incidence of cardiovascular mortality by sex. Abbreviation: G3b-5, glomerular filtration rate categories 3b to G5.

      Discussion

      This study presents 10-year results from a national Swedish registry for patients with CKD who were not on dialysis. We found that the overall rate of CKD progression was 19.6% per year. Men had a higher risk of progression, a steeper eGFR decline, and a higher risk of death, especially cardiovascular mortality, prior to KRT than women.
      There have been several previous reports of sex differences in CKD progression. Observational studies of more selected CKD populations have mostly demonstrated slower decline in eGFR in women than men.
      • Eriksen B.O.
      • Ingebretsen O.C.
      The progression of chronic kidney disease: a 10-year population-based study of the effects of gender and age.
      ,
      • Halbesma N.
      • Brantsma A.H.
      • Bakker S.J.
      • et al.
      Gender differences in predictors of the decline of renal function in the general population.
      However, a meta-analysis by Jafar et al
      • Jafar T.H.
      • Schmid C.H.
      • Stark P.C.
      • et al.
      The rate of progression of renal disease may not be slower in women compared with men: a patient-level meta-analysis.
      presented a higher risk of progression in women when using doubling in serum creatinine or progression to KRT as end points. In the Chronic Renal Insufficiency Cohort (CRIC) study,
      • Ricardo A.C.
      • Yang W.
      • Sha D.
      • et al.
      Sex-related disparities in CKD progression.
      on the other hand, women were less likely to start KRT, to experience a decrease in eGFR by 50% from baseline, and to progress to CKD G5. More recently, Minutolo et al
      • Minutolo R.
      • Gabbai F.B.
      • Chiodini P.
      • et al.
      Sex differences in the progression of CKD among older patients: pooled analysis of 4 cohort studies.
      studied the effect of sex on CKD progression using time to KRT, eGFR slope, and mortality in 4 referred CKD cohorts in Italy. In line with our findings, that study showed a significantly higher risk of progression in men than women. The adjusted eGFR slope was −1.79 mL/min/1.73 m2 per year in women and −2.09 mL/min/1.73 m2 per year in men, again comparable with our results. Moreover, we found differences in eGFR slopes between patients with different primary kidney diseases, also consistent with earlier findings.
      • Brosnahan G.M.
      • Abebe K.Z.
      • Moore C.G.
      • et al.
      Determinants of progression in early autosomal dominant polycystic kidney disease: is it blood pressure or renin-angiotensin-aldosterone-system blockade?.
      ,
      • Haynes R.
      • Staplin N.
      • Emberson J.
      • et al.
      Evaluating the contribution of the cause of kidney disease to prognosis in CKD: results from the Study of Heart and Renal Protection (SHARP).
      The reason for potential sex-related differences in the progression of CKD is not known, but differences in underlying risk factors and the effect of sex hormones have been proposed.
      • Carrero J.J.
      • Hecking M.
      • Chesnaye N.C.
      • Jager K.J.
      Sex and gender disparities in the epidemiology and outcomes of chronic kidney disease.
      For example, animal studies have shown protective, anti-inflammatory responses of estrogens on podocytes
      • Catanuto P.
      • Doublier S.
      • Lupia E.
      • et al.
      17 beta-estradiol and tamoxifen upregulate estrogen receptor beta expression and control podocyte signaling pathways in a model of type 2 diabetes.
      and permeability-reducing effects in glomerular endothelium.
      • Hutchens M.P.
      • Fujiyoshi T.
      • Komers R.
      • Herson P.S.
      • Anderson S.
      Estrogen protects renal endothelial barrier function from ischemia-reperfusion in vitro and in vivo.
      In our study however, no differences were found between the decline of eGFR in women and that in men before and after the mean menopausal age for women in Sweden.
      Population-based studies have indicated that women are more represented than men in earlier stages of CKD,
      • Hill N.R.
      • Fatoba S.T.
      • Oke J.L.
      • et al.
      Global prevalence of chronic kidney disease – a systematic review and meta-analysis.
      ,
      • Murphy D.
      • McCulloch C.E.
      • Lin F.
      • et al.
      Trends in prevalence of chronic kidney disease in the United States.
      whereas men are overrepresented in later CKD stages
      • Carrero J.J.
      • Hecking M.
      • Chesnaye N.C.
      • Jager K.J.
      Sex and gender disparities in the epidemiology and outcomes of chronic kidney disease.
      and in dialysis populations.
      • Hecking M.
      • Bieber B.A.
      • Ethier J.
      • et al.
      Sex-specific differences in hemodialysis prevalence and practices and the male-to-female mortality rate: the Dialysis Outcomes and Practice Patterns Study (DOPPS).
      One explanation for the higher proportion of men in CKD G3b in this study, despite a higher population prevalence of CKD G3 in women in Sweden, could be that men are referred to a nephrologist more often than women.
      • Ricardo A.C.
      • Roy J.A.
      • Tao K.
      • et al.
      Influence of nephrologist care on management and outcomes in adults with chronic kidney disease.
      The reason for this, despite equal referral guidelines for men and women, could be a focus on serum creatinine rather than eGFR (which at equal eGFR is higher in men than in women) but could also depend on the higher risk of progression and the generally higher albuminuria levels among men.
      • Zhuo M.
      • Jiang M.Y.
      • Song R.
      • et al.
      High prevalence and low awareness of albuminuria in the community setting in the KDSAP.
      Differences in levels of albuminuria between men and women were also observed in our cohort. Also, in secondary analyses when we adjusted for albuminuria, the differences in risk of CKD progression approached unity, although the eGFR slope remained steeper in men. This suggests that albuminuria mediates at least some of the differences in CKD progression between men and women. Other explanations for the observed sex differences such as differences in eGFR accuracy or in the frequency of follow-up were not supported by our data or previous studies.
      • Evans M.
      • van Stralen K.J.
      • Schön S.
      • et al.
      Glomerular filtration rate-estimating equations for patients with advanced chronic kidney disease.
      In our cohort, we observed a higher proportion of patients with glomerular diseases than in most other cohort studies, probably because SRR-CKD is a cohort of referred nephrology patients, not a general population or risk cohort. In line with most other studies, our results indicate that old age is associated with slower eGFR decline and a lower risk of progression from earlier CKD stages. It is possible that younger patients have more aggressive types of primary kidney diseases or more severe forms. In a meta-analysis by the CKD Prognosis Consortium, young age was associated with an increased risk of KRT and faster decline of eGFR, after adjusting for albuminuria.
      • Coresh J.
      • Turin T.C.
      • Matsushita K.
      • et al.
      Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality.
      Earlier findings also suggest old age is associated with a decreased risk of dialysis or kidney transplantation,
      • Evans M.
      • Grams M.E.
      • Sang Y.
      • et al.
      Risk factors for prognosis in patients with severely decreased GFR.
      although that could partly be explained by medical decisions to treat elderly patients more conservatively.
      • Yang W.
      • Xie D.
      • Anderson A.H.
      • et al.
      Association of kidney disease outcomes with risk factors for CKD: findings from the Chronic Renal Insufficiency Cohort (CRIC) study.
      ,
      • De Nicola L.
      • Chiodini P.
      • Zoccali C.
      • et al.
      Prognosis of CKD patients receiving outpatient nephrology care in Italy.
      We have no information in the present study for whether men and women were offered or accepted KRT to the same extent, but an earlier study suggests that women may be more likely to receive conservative treatment.
      • Morton R.L.
      • Turner R.M.
      • Howard K.
      • Snelling P.
      • Webster A.C.
      Patients who plan for conservative care rather than dialysis: a national observational study in Australia.
      In this study, we observed better survival in women, although the results were not consistently statistically significant through all CKD stages. Similar results for all-cause mortality were obtained by Minutolo et al, although with a lower precision.
      • Minutolo R.
      • Gabbai F.B.
      • Chiodini P.
      • et al.
      Sex differences in the progression of CKD among older patients: pooled analysis of 4 cohort studies.
      Although other studies have seen inferior survival for women in CKD G5 compared to that in men,
      • Faruque L.I.
      • Hemmelgarn B.R.
      • Wiebe N.
      • et al.
      Factors associated with initiation of chronic renal replacement therapy for patients with kidney failure.
      we observed similar results for men and women in CKD G5. Again, our results may differ due to lower survival bias than those of others, where healthy male survivors/slow progressors among prevalent cohorts may influence the estimates. Our results, based upon incident CKD cases, indicate that women have a lower unadjusted risk of both progression and mortality. This suggests that women survive longer in earlier CKD stages, potentially explaining the observed equal—or sometimes higher—cross-sectional prevalence of earlier-stage CKD in women.
      Among the strengths of this study is that, to our knowledge this is the first follow-up study of a nationwide, well-characterized cohort of referred CKD patients showing transition patterns from CKD G3b to G5 over a 10-year period. The repeated outpatient visits allowed for eGFR slope analysis and risk analyses over time. The inclusion of incident cases per CKD stage minimized that survival bias of prevalent survivors. Furthermore, there were no losses to follow-up regarding initiation of KRT and mortality.
      There are also some limitations. Information about whether the diagnosis was based on a kidney biopsy or not was not mandatory until 2013. The SRR-CKD only records outpatient nephrology visits, and although information for KRT initiation is always collected, eGFR assessed outside of nephrology practice are not included. We do not believe that this substantially impacted the results, as Sweden has publicly funded health care that is equally accessible for both sexes. Furthermore, the national guidelines for referral to a specialist in nephrology do not differ by sex. eGFR is now reported directly by most laboratories. Previous reports from Sweden show that, in the largest region, more than 90% of those older than 65 years of age were tested at least once over a 6-year period.
      • Runesson B.
      • Gasparini A.
      • Qureshi A.R.
      • et al.
      The Stockholm CREAtinine Measurements (SCREAM) project: protocol overview and regional representativeness.
      However, the absolute incidence of CKD progression may be lower among nonreferred persons in general, as a more rapid decline in eGFR or high level of albuminuria are among nephrology referral criteria. Similarly, the rates of progression are not directly comparable between CKD G3b and G4-G5 as most patients are not referred or included in the SRR-CKD until eGFR has dropped below 40 mL/min/1.73 m2. However, this would not impact the comparison between sexes, as we found no differences in eGFR at inclusion or in the number of visits between men and women during follow-up. Although coverage was high, some regions reported less frequently to the registry than others, which could influence the results if those regions had a different age and sex distribution. Previous reports from SRR-CKD have not indicated any major regional differences regarding case-mix, and eGFR slopes are quite similar across the country.
      • Evans M.
      Kronisk njursjukdom. Årsrapport Svenskt Njurregister [Chronic Kidney Disease. Annual Report Swedish Renal Registry].
      Finally, the Swedish population is mostly of European ancestry, therefore our results may not be generalizable to other populations.
      In conclusion, this study describes the 10-year data from a nationwide registry of incident CKD patients in Sweden. The study identifies age, sex, albuminuria, and primary kidney disease to be associated with CKD progression and eGFR slope. Overall, women have a lower risk of both CKD progression and all-cause and cardiovascular mortality than men. Identifying factors associated with a higher rate of disease progression is important so that preventive measures may be taken.

      Article Information

      Authors’ Full Names and Academic Degree

      Oskar Swartling, MD, Helena Rydell, MD, PhD, Maria Stendahl, MD, PhD, Mårten Segelmark, MD, PhD, Ylva Trolle Lagerros, MD, PhD, and Marie Evans, MD, PhD.

      Authors’ Contributions

      Concept and design: all authors; statistical analysis: OS, ME; interpretation of results: all authors. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for the individual’s own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved, including with documentation in the literature if appropriate.

      Support

      Dr Swartling has received support from the Clinical Scientist Training Programme (CSTP) and a research internship at Karolinska Institutet. Dr Evans was funded by a grant from Center for Innovative Medicine at Karolinska (CIMED), and Stockholm City Council (ALF Medicine). No funders had any role in study design, data collection, analysis, reporting, or the decision to submit for publication.

      Financial Disclosure

      Outside the submitted work, Dr Evans is a compensated lecturer for Astellas, Vifor Pharma, and Fresenius; and is a member of advisory boards for Astra Zeneca, Vifor Pharma, and Astellas; and has received institutional grants for other studies from AstraZeneca and Astellas, and travel grants from Baxter. The other authors declare they have no relevant financial interests.

      Acknowledgements

      The authors thank the contributing centers of the Swedish Renal Registry for their ongoing work with the registry.

      Peer Review

      Received May 21, 2020. Evaluated by 2 external peer reviewers, with direct editorial input from a Statistics/Methods Editor, an Associate Editor, and the Editor-in-Chief. Accepted in revised form November 21, 2020.

      Supplementary Material

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