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Diabetic foot disease in subjects with End-stage renal Disease: A nationwide study over 14 years highlighting an emerging threat

  • Cheng-Wei Lin
    Affiliations
    Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan
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  • David G. Armstrong
    Affiliations
    Southwestern Academic Limb Salvage Alliance (SALSA), Department of Surgery, Keck School of Medicine of University of Southern California (USC), Los Angeles, USA (D.G.A.)
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  • Chung-Huei Huang
    Affiliations
    Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan
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  • Chia-Hung Lin
    Affiliations
    Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan
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  • Shih-Yuan Hung
    Affiliations
    Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Pi-Hua Liu
    Correspondence
    Corresponding authors.
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan

    Clinical Informatics and Medical Statistics Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Yu-Yao Huang
    Correspondence
    Corresponding authors.
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan

    College of Medicine, Chang Gung University, Taoyuan City, Taiwan

    Department of Medical Nutrition Therapy, Chang Gung Memorial Hospital, Taoyuan City, Taiwan
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  • Author Footnotes
    1 These authors contributed equally to this work.
Open AccessPublished:October 28, 2022DOI:https://doi.org/10.1016/j.diabres.2022.110134

      Highlights

      • This nationwide study revealed annual prevalence of subjects with end-stage renal disease (ESRD) has increased some 3.9-fold over 14 years.
      • These ESRD patients now account for approximately 30% of annual major-LEA of the total diabetic foot disease (DFD) population.
      • Peripheral arterial disease was the major difference of foot presentation compared to those of without ESRD.
      • The increase of endovascular treatments (EVTs) was associated with a reduction in rate of limb loss.
      • People with diabetes and ESRD should be educated to prevent foot ulcers and the interdisciplinary team approach is indicated if DFD complicated.

      Abstract

      Aims

      To disclose prevalence, demographic, foot characteristics as well as management and lower-extremity amputations (LEAs) of subjects with end-stage renal disease (ESRD) on diabetic foot diseases (DFDs).

      Methods

      Data were derived from the Taiwan National Health Insurance Research Database between 2004 and 2017. DFDs were defined as ulcers, infections, or severe peripheral arterial diseases (PADs) in patients with type 2 diabetes. Clinical characteristics were analyzed between subjects with and without ESRD.

      Results

      Subjects with ESRD have increased impacts on the DFD population either from annual prevalence (2.7 % to 10.42 %, P for trend < 0.001), or proportional representation in LEAs (7.91 % to 26.37 %, P < 0.001) over 14 years. The annual trends for major-LEAs rates have decreased in both subjects with and without ESRD (13.67 % to 5.82 % and 3.48 % to 1.47 %, both P < 0.001). Notably, the concomitant increase of endovascular treatments (EVTs) (7.09 % to 29.41 %, P < 0.001) was associated with the decrease of major-LEAs (P for interaction < 0.001) in subjects with ESRD.

      Conclusions

      As the annual prevalence of subjects with ESRD has increased 3.9-fold over years, they now account for more than 30% of annual major-LEA of the total DFD population. Interdisciplinary team approach and aggressive EVTs might reduce major-LEAs in these patients.

      Keywords

      Abbreviations:

      ESRD (End-stage renal disease), DFD (Diabetic foot disease), LEA (Lower-extremity amputation), PAD (Peripheral arterial disease), EVT (Endovascular treatment)

      1. Introduction

      The major etiology of end-stage renal disease (ESRD) is attributed to diabetes worldwide [
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      It has been reported that hyperglycemia, hypertension, and chronic kidney disease are associated with foot ulcer development in patients with diabetes [
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      ]. Furthermore, ESRD in patients requiring dialysis is an independent risk factor for foot ulcer in patients with diabetes and increases the incidence of LEA risk [
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      ]. Notably, the presence of ESRD interferes with wound-healing in a combination of processes, including vascular problems either from atherosclerosis [
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      ] or accelerated calcification of vessels [
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      ], the adverse effects of uremia on fibroblast proliferation, hydroxyproline level and collagen production in wounds [
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      ], and loss of nutrients [
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      ], etc. Hospital treatment for foot-related diseases is therefore frequent for these patients [
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      Amputations and foot-related hospitalisations disproportionately affect dialysis patients.
      ], moreover, poor survival is noted among these ESRD patients suffering from foot disease [
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      ].
      Because of the robust and comprehensive nature of the Taiwan National Health System database, we are able to report the characteristics of the DFD population between years 2007 and 2014 [
      • Lin C.-W.
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      • et al.
      Nationwide trends in the epidemiology of diabetic foot complications and lower-extremity amputation over an 8-year period.
      ]. As the type 2 diabetes population rose from 1,115,556 to 1,556,988 (between year 2007 and 2014), the number of people with DFDs increased from 23,068 to 30,783 with an increasing ratio by 33.4 % [
      • Lin C.-W.
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      • et al.
      Nationwide trends in the epidemiology of diabetic foot complications and lower-extremity amputation over an 8-year period.
      ].
      The United States has previously reported a decreasing trend in LEAs in recent years for adults with diabetes with LEA rates per 1,000 subjects around 5.38 to 4.62 (year 2000 to 2015) [
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      ]. Though higher LEA rates are noted, similar decreasing trends have been reported in people with diabetes and ESRD [
      • Franz D.
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      ]. Accordingly, people with ESRD and developed DFDs are supposed to have poor clinical processes but contemporary evidence is lacking, so information regarding foot disease phenotypes or limb preservation among patients with DFDs and ESRD is required for further investigations.
      The present study was conducted to better understand the prevalence and time trends of patients who were concomitant with DFDs and ESRD between 2004 and 2017, including their demographics, affected foot and major procedures introduced to treat these patients, and LEAs.

      2. Subjects, materials, and methods

      2.1 Study population and source

      The present study was based on data collected over a 14-year period (2004 to 2017) derived from the Taiwan National Health Insurance Research Database (NHIRD). The Taiwanese government implemented its National Health Insurance (NHI) system in 1995. This provided coverage for 95 % of the population in 2000, which increased to 98 % in 2005 and 99.6 % of the total 23 million people in Taiwan in 2009 [
      • Lin C.-W.
      • Armstrong D.G.
      • Lin C.-H.
      • Liu P.-H.
      • Hung S.-Y.
      • Lee S.-R.
      • et al.
      Nationwide trends in the epidemiology of diabetic foot complications and lower-extremity amputation over an 8-year period.
      ,
      • Huang Y.-Y.
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      • Jiang Y.-D.
      • Chang C.-H.
      • Chung C.-H.
      • Chuang L.-M.
      • et al.
      Diabetes-related kidney, eye, and foot disease in Taiwan: an analysis of the nationwide data for 2000–2009.
      ,
      • Lin C.H.
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      • Liu P.H.
      • Lin C.W.
      • Huang C.H.
      • Huang Y.Y.
      Survival of Patients Following First Diagnosis of Diabetic Foot Complications: a Nationwide 15-Year Longitudinal Analysis.
      ]. Large computerized administrative and claims data sets derived from this program have provided diagnoses, procedures, and prescriptions of inpatient and outpatient records. Patients with type 2 diabetes mellitus were identified through the ICD-9 diagnostic code of 250 (except 250.01, 250.03 for type 1 diabetes) during 2004 to 2015 and ICD-10 code of E11 in 2016 and 2017 at least once during hospital admission or three or more times for ambulatory clinic patients in each calendar year. The ESRD was identified by diagnostic codes and defined as having renal failure status requiring chronic dialysis therapy. The Chang Gung Medical Foundation Institutional Review Board approved this study (No. 201801421A3C501) and its reporting conforms to the STROBE guidelines [
      • von Elm E.
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      • Egger M.
      • Pocock S.J.
      • Gotzsche P.C.
      • Vandenbroucke J.P.
      • et al.
      The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.
      ].

      2.2 Definition of diabetic foot diseases and comorbidities

      The identifications of diagnoses for foot diseases and comorbidities are according to the diagnostic codes (ICD-9 from 2004 to 2015 and ICD-10 in 2016 and 2017) as presented in Supplementary Appendix 1, including diabetic foot infection, severe peripheral arterial diseases (PADs) and foot ulcers. The diabetic foot infections were identified by foot cellulitis/abscess, osteomyelitis and necrotizing fasciitis, while severe PADs were identified by the presentation of foot gangrene or hospitalization for treatment of PAD. Lower-extremity amputations were identified by diagnostic codes or procedure codes (Supplementary Appendix 1). Only the highest-level amputation was enrolled for per-patient-per-calendar-year measure to prevent overestimation of the amputation amount because of possible multistep procedures for one person. The comorbidities of patients with DFDs were identified based on the records of coding for hypertension, dyslipidemia, coronary heart diseases, and cerebral vascular accidents before the diagnosis of DFDs.

      2.3 Vascular interventions

      The endovascular treatments (EVTs) were defined by the procedure codes for percutaneous transluminal angioplasty (PTAs), either simple PTA (33074B) or complicated PTA (33115B), with bypass graft surgery defined by code of 69004B. These specific procedure codes of NHIRD are provided in Supplementary Appendix 2.

      2.4 Statistical analysis

      Demographic characteristics including age, gender, and comorbidities among DFD patients with/without ESRD were summarized by year using frequencies (proportions) and means (standard deviation [SD]) as appropriate, with the prevalence described as a percentage. Within the population of people coded with DFDs, the prevalence and the proportion of the comorbidities, LEAs, phenotypes of foot diseases including severe PADs, foot infections and foot ulcers, and vascular interventions were analyzed annually, while changes in the prevalence and proportion from 2007 to 2014 were analyzed using a join-point regression model with annual percent changes (APC) reported. All statistical analyses were performed using the SAS version 9.4 (SAS Institute, Inc., Cary, NC) and the Join-point Trend Analysis Software version 4.5.0.1.

      3. Results

      3.1 Trends of prevalence and clinical characteristics

      The absolute number of the DFD population having ESRD increased from 578 in year 2004 to 3,108 in 2017 (Table 1). Beyond the absolute number, the ESRD prevalence further increased from 2.7 % to 10.42 % (APC 7.88 [95 % confidence interval 5.85, 9.949], P for trend < 0.001) among the population with DFDs. The proportion of ESRD in patients suffering from LEAs also increased over these years (7.91 % to 26.37 %, APC 6.78 [4.598, 9.007], P for trend < 0.001), either in minor-LEA (6.33 to 23.39 %, APC 7.626 [5.085, 10.228], P for trend < 0.001) or major-LEA (9.84 to 31.53 %, APC 6.327 [4.268, 8.427], P for trend < 0.001).
      Table 1The trends of patients with ESRD and DFD is increasing both in prevalence and LEAs.
      Year20042005200620072008200920102011201220132014201520162017APC (95 % CI)

      P for trend
      ESRD subjects5787949491,1421,3481,6191,9282,1632,2052,1792,2092,3383,0753,108
      Total DFD patients21,38422,53722,39623,20324,36025,36526,48827,30027,52227,87327,98229,14632,00029,816
      (% of patients from ESRD)(2.7)(3.52)(4.24)(4.92)(5.53)(6.38)(7.28)(7.92)(8.01)(7.82)(7.89)(8.02)(9.61)(10.42)7.880 (5.850 – 9.949)

       < 0.001
      LEA of patients with ESRD141214239299327358418401382367411397464414
      LEAs of total DFD patients1,7821,9281,7891,9121,9141,8751,8471,9181,7381,6931,7301,7771,7191,570
      (% LEA from ESRD)(7.91)(11.10)(13.36)(15.64)(17.08)(19.09)(22.63)(20.91)(21.98)(21.68)(23.76)(22.34)(26.99)(26.37)6.780 (4.598 – 9.007)

       < 0.001
      Minor-LEA of patients with ESRD6294104126147176207205207199215225258233
      Minor-LEAs of total DFD patients9791,0519539881,0271,0201,0241,0799549879951,0581,060996
      (% Minor-LEA from ESRD)(6.33)(8.94)(10.91)(12.75)(14.31)(17.25)(20.21)(19.00)(21.70)(20.16)(21.61)(21.27)(24.34)(23.39)7.626 (5.085 – 10.228)

       < 0.001
      Major-LEA of patients with ESRD79120135173180182211196175168196172206181
      Major-LEAs of total DFD patients803877836924887855823839784706735719659574
      (% Major-LEA from ESRD)(9.84)(13.68)(16.15)(18.72)(20.29)(21.29)(25.64)(23.36)(22.32)(23.80)(26.67)(23.92)(31.26)(31.53)6.327 (4.268 – 8.427)

       < 0.001
      In Table 2, characteristics and foot presentations of patients with DFD and ESRD are described. Increasing older age with mean age of 64.97 ± 11.34 years in 2004 and 66.26 ± 11.86 years in 2017 (P for trend = 0.007) was noted, as was an increasing trend in male gender (50.35 % to 55.73 %, APC 0.935 [0.603, 1.269], P for trend < 0.001). The trends of comorbidities in these patients were noted as remaining stable for high prevalence in hypertension (64.36 % to 64.09 %, APC − 1.062 [-2.957, 0.871], P for trend = 0.252) and coronary heart diseases (10.55 % to 9.78 %, APC − 0.679 [-3.963, 2.717], P for trend = 0.667), increasing trend in dyslipidemia (27.68 % to 40.51 %, APC 2.681 [1.721, 3.65], P for trend < 0.001), but decreasing in ischemic stroke (1.73 % to 0.61 %, APC − 9.056 [−13.106, −4.817], P for trend = 0.001) and hemorrhagic stroke (0.17 % to 0.06 %, APC − 12.248 [-20.126, −3.581], P for trend = 0.011). In comparison to ESRD patients, the non-ESRD subjects had less comorbidities with hypertension (46.9 % to 48.85 %, APC 0.606 [-0.405, 1.627], P for trend = 0.217) and coronary heart diseases (5.5 % to 5.09 %, APC − 1.384 [-1.924, −0.822], P for trend < 0.001), but slightly more in ischemic stroke (2.1 % to 1.52 %, APC − 2.676 [-3.351, −1.996], P for trend < 0.001), hemorrhagic stroke (0.13 % to 0.21 %, APC 3.534 [0.656, 6.495], P for trend = 0.02) and dyslipidemia (27.18 % to 54.45 %, APC 5.763 [5.269, 6.259], P for trend < 0.001) (Fig. 1 and Supplementary Appendix 3).
      Table 2Trends of clinical characteristics and foot presentations of patients with ESRD and DFDs.
      Year20042005200620072008200920102011201220132014201520162017APC (95 % CI)

      P for trend
      Age (mean ± SD)64.97 ± 11.3464.63 ± 11.3265.05 ± 11.1665.87 ± 11.2866.19 ± 11.4266.24 ± 11.666.66 ± 11.8766.69 ± 11.6666.58 ± 11.7566.87 ± 11.8567.25 ± 11.7767.12 ± 11.9565.62 ± 11.7366.26 ± 11.860.205 (0.068, 0.341)

      0.007
      Male gender291 (50.35)412 (51.89)475 (50.05)591 (51.75)700 (51.93)858 (53)996 (51.66)1,115 (51.55)1,224 (55.51)1,206 (55.35)1,197 (54.19)1,320 (56.46)1,734 (56.39)1,732 (55.73)0.935 (0.603, 1.269)

       < 0.001
      Comorbidities, n (%)
      Hypertension372 (64.36)568 (71.54)721 (75.97)897 (78.55)1,113 (82.57)1,331 (82.21)1,617 (83.87)1,829 (84.56)1,873 (84.94)1,833 (84.12)1,863 (84.34)1,962 (83.92)1,929 (62.73)1,992 (64.09)−1.062 (-2.957, 0.871)

      0.252
      Dyslipidemia160 (27.68)245 (30.86)257 (27.08)354 (31)468 (34.72)557 (34.4)704 (36.51)805 (37.22)808 (36.64)826 (37.91)940 (42.55)984 (42.09)1,193 (38.8)1,259 (40.51)2.681 (1.721, 3.650)

       < 0.001
      Coronary heart disease61 (10.55)99 (12.47)116 (12.22)147 (12.87)158 (11.72)219 (13.53)219 (11.36)276 (12.76)324 (14.69)337 (15.47)325 (14.71)363 (15.53)259 (8.42)304 (9.78)−0.679 (-3.963, 2.717)

      0.667
      Ischemic stroke10 (1.73)16 (2.02)27 (2.85)18 (1.58)29 (2.15)35 (2.16)21 (1.09)33 (1.53)40 (1.81)21 (0.96)25 (1.13)30 (1.28)18 (0.59)19 (0.61)−9.056 (-13.106, −4.817)

      0.001
      Hemorrhagic stroke1 (0.17)6 (0.76)3 (0.32)3 (0.26)1 (0.07)4 (0.25)2 (0.1)3 (0.14)3 (0.14)1 (0.05)2 (0.09)6 (0.26)1 (0.03)2 (0.06)−12.248 (-20.126, −3.581)

      0.011
      Foot presentations, n (%)
      Foot infections167 (28.89)260 (32.75)323 (34.04)402 (35.2)464 (34.42)572 (35.33)710 (36.83)756 (34.95)788 (35.74)747 (34.28)741 (33.54)846 (36.18)1,291 (41.98)1,313 (42.25)1.917 (0.855, 2.990)

      0.002
      Cellulitis and abscess113 (19.55)162 (20.4)217 (22.87)239 (20.93)291 (21.59)359 (22.17)426 (22.1)489 (22.61)474 (21.5)452 (20.74)488 (22.09)565 (24.17)1,167 (37.95)1,190 (38.29)5.792 (2.831, 8.838)

      0.001
      Osteomyelitis20 (3.46)45 (5.67)51 (5.37)62 (5.43)67 (4.97)95 (5.87)122 (6.33)120 (5.55)113 (5.12)141 (6.47)123 (5.57)156 (6.67)366 (11.9)352 (11.33)8.323 (4.503, 12.281)

       < 0.001
      Necrotizing fasciitis32 (5.54)40 (5.04)44 (4.64)59 (5.17)68 (5.04)106 (6.55)124 (6.43)148 (6.84)168 (7.62)158 (7.25)155 (7.02)183 (7.83)232 (7.54)232 (7.46)3.438 (2.089, 4.804)

       < 0.001
      PADs295 (51.04)370 (46.6)469 (49.42)576 (50.44)701 (52)882 (54.48)1,053 (54.62)1,205 (55.71)1,242 (56.33)1,262 (57.92)1,280 (57.94)1,327 (56.76)1,566 (50.93)1,630 (52.45)0.475 (-0.454, 1.413)

      0.288
      Gangrene114 (19.72)138 (17.38)180 (18.97)182 (15.94)222 (16.47)247 (15.26)320 (16.6)322 (14.89)290 (13.15)283 (12.99)272 (12.31)295 (12.62)733 (23.84)797 (25.64)2.979 (-0.982, 7.098)

      0.129
      −2.019 (-3.383, −0.635)
      Foot ulcers125 (21.63)185 (23.3)198 (20.86)230 (20.14)236 (17.51)265 (16.37)312 (16.18)362 (16.74)319 (14.47)347 (15.92)363 (16.43)394 (16.85)538 (17.5)475 (15.28)0.008
      Figure thumbnail gr1
      Fig. 1Rates of comorbidities in patients with DFDs between having ESRD and non-ESRD.In comparison to ESRD patients, the non-ESRD subjects had less comorbidities with hypertension and coronary heart diseases, but slightly more in cerebral vascular accidents and dyslipidemia.

      3.2 Foot disease presentations

      The presentations of DFDs over time in patients with ESRD were predominant in severe PADs with non-specific increase (from 51.04 % to 52.45 %, APC 0.475 [-0.454, 1.413], P for trend = 0.288); nevertheless, the presence of foot gangrene decreased from 19.72 % to 12.62 % during 2004 to 2015 but became elevated to 23.84 % and 25.64 % in 2016 and 2017 when the ICD code was transformed from version 9 to 10. The rate for foot infection also increased from 28.89 % in 2004 to 42.25 % in 2017 with increasing trend (APC 1.917 [0.855, 2.99], P for trend = 0.002) seen as well as in severe infection phenotypes (3.46 % to 11.33 %, APC 8.323 [4.503, 12.281] in osteomyelitis with P for trend < 0.001 and 5.54 % to 7.46 %, APC 3.438 [2.089, 4.804] in necrotizing fasciitis with P for trend < 0.001 respectively). Though the absolute number increased, the trend of foot ulcer presentations decreased (21.63 % to 15.28 %, APC − 2.019 [-3.383, −0.635], P for trend = 0.008).
      Fig. 2 illustrates the discrepancy of phenotypes of DFDs between patients with and without ESRD over the years. It is noted that the PAD problems in patients with ESRD were around 2-fold to non-ESRD subjects (51.04 % to 52.45 % vs 25.27 % to 22.15 % respectively). In contrast, though both had increasing trend, non-ESRD patients presented more cellulitis/abscess 1.5- to 2-fold compared to ESRD subjects (41.12 % to 61.13 % vs 19.55 % to 38.29 % respectively). Regarding severe foot infection however, both patients with or without ESRD shared similar proportions of osteomyelitis and necrotizing fasciitis.
      Figure thumbnail gr2
      Fig. 2Rates of individual foot presentations in patients with DFDs between having ESRD and non-ESRD. The severe PADs in patients with ESRD were around 2-fold to non-ESRD subjects. In contrast, non-ESRD patients presented more cellulitis/abscess 1.5- to 2-fold compared to ESRD subjects. Both groups shared similar proportions of osteomyelitis and necrotizing fasciitis.

      3.3 Vascular interventions and limb salvage

      Because of the high prevalence of PAD in patients with ESRD, the contemporary data for vascular treatment were analyzed and a continual increase of total vascular interventions was noted from 8.82 % in 2004 to 31.15 % in 2017. This was primarily due to increase in EVT (7.09 % to 29.41 %, APC 9.318 [7.098, 11.584], P for trend < 0.001) rather than bypass surgery (1.73 % to 1.74 %, APC − 5.461 [-9.084, −1.693], P = 0.01) (Fig. 3). The proportion and increased trend of EVT (0.66 % to 3.99 %, APC 9.955 [5.156, 14.974], P for trend = 0.001) among non-ESRD patients was not as obvious as ESRD patients, and the bypass surgery rate declined over time (1.14 % to 0.33 %, APC − 10.083 [-12.209, −7.905], P for trend < 0.001). Under such treatment, though with elevated numbers of LEAs, the trend of LEAs rates in patients with ESRD decreased over years (24.39 % to 13.32 %, APC − 5.161 [-6.165, −4.145], P for trend < 0.001), particularly in major-LEA with more obvious decline than non-ESRD patients (13.67 % to 5.82 % vs 3.48 % to 1.47 % respectively, P for interaction < 0.001). The trend of decreasing major-LEA in patients with ESRD was further noted as associated with concomitant rising amounts of endovascular treatments (13.67 % to 5.82 % vs 7.09 % to 29.41 %, P for interaction < 0.001).
      Figure thumbnail gr3
      Fig. 3The trends of (A) LEAs and (B) vascular intervention procedures between patients with ESRD or without ESRD.The trend of prominent rising rates of EVT (7.09 % to 29.41 %, P for trend < 0.001) in patients with ESRD (A) was further noted as associated with concomitant decreasing major-LEA rates (13.67 % to 5.82 %, P for trend < 0.001) among them (B) (P for interaction < 0.001).

      4. Discussions

      This nationwide study revealed contiguous increase in either number or proportion of patients concomitant with ESRD in the DFD population, with a nearly fourfold increase during the 14 years (578 to 3,108 and 2.70 % to 10.42 % respectively). Owing to improvements in medicine, more diabetic patients have a longer lifespan to reach ESRD. This is a serious problem because the patients with ESRD further accounted for more and more LEAs to the general DFD population over these years, either in minor-LEA (6.33 to 23.39 %) or major-LEA (9.84 to 31.53 %); however, an interesting issue is whether the increased number of DFD patients with ESRD is owing to the ongoing increased prevalence of ESRD in Taiwan [
      • Thurlow J.S.
      • Joshi M.
      • Yan G.
      • Norris K.C.
      • Agodoa L.Y.
      • Yuan C.M.
      • et al.
      Global epidemiology of end-stage kidney disease and disparities in kidney replacement therapy.
      ] or increased DFD problems in ESRD patients. Another nationwide study in Taiwan from 2005 to 2014 disclosed increased numbers of ESRD patients with diabetes from 17,531 to 32,441 [
      • Lin K.D.
      • Hsu C.C.
      • Ou H.Y.
      • Wang C.Y.
      • Chin M.C.
      • Shin S.J.
      Diabetes-related kidney, eye, and foot disease in Taiwan: an analysis of nationwide data from 2005 to 2014.
      ]. Given the reference above and our data, the rough ratio of DFD in patients with ESRD increased from 4.53 % (794/17,531) to 7.21 % (2,338/32,441) from 2005 to 2014, which indicated an emerging health issue of DFD in subjects with ESRD, also posing an increased challenge in treating DFD because of higher levels of associated comorbidities in patients with ESRD, particularly in cardiovascular complications.
      Via the national claims data source, the major difference in clinical DFD presentation among subjects with and without ESRD was the prevalence of severe PAD. It is recognized that patients concomitant with diabetes and kidney disease have increased risk of PAD [
      • Aziz K.M.
      Diabetic foot ulcer risk with diabetic kidney disease and renal failure among 10,680 patients.
      ], while PAD has been reported more in subjects who went through ESRD [
      • Tsai C.-Y.
      • Chu S.-Y.
      • Wen Y.-W.
      • Hsu L.-A.
      • Chen C.-C.
      • Peng S.-H.
      • et al.
      The value of Doppler waveform analysis in predicting major lower extremity amputation among dialysis patients treated for diabetic foot ulcers.
      ]. The mechanism of PAD in patients with ESRD was suspected as associating with atherosclerosis by advanced glycation end products [
      • Aronson D.
      • Rayfield E.J.
      How hyperglycemia promotes atherosclerosis: molecular mechanisms.
      ,
      • Ahmed N.
      Advanced glycation endproducts–role in pathology of diabetic complications.
      ] and vascular calcification [
      • Tsai C.-Y.
      • Chu S.-Y.
      • Wen Y.-W.
      • Hsu L.-A.
      • Chen C.-C.
      • Peng S.-H.
      • et al.
      The value of Doppler waveform analysis in predicting major lower extremity amputation among dialysis patients treated for diabetic foot ulcers.
      ] by multiple risk factors including uremia toxin [
      • Hoyer F.F.
      • Nahrendorf M.
      Uremic Toxins Activate Macrophages.
      ,
      • Wojtaszek E.
      • Oldakowska-Jedynak U.
      • Kwiatkowska M.
      • Glogowski T.
      • Malyszko J.
      • Karolczak K.
      Uremic toxins, oxidative stress, atherosclerosis in chronic kidney disease, and kidney transplantation.
      ] and abnormal mineral metabolism [
      • Maroz N.
      • Simman R.
      Wound Healing in Patients With Impaired Kidney Function.
      ], etc. Beyond the poor peripheral circulation, the ESRD itself was further considered to be an independent risk factor of LEA [
      • Otte J.
      • van Netten J.J.
      • Woittiez A.J.
      The association of chronic kidney disease and dialysis treatment with foot ulceration and major amputation.
      ,
      • Morbach S.
      • Quante C.
      • Ochs H.R.
      • Gaschler F.
      • Pallast J.M.
      • Knevels U.
      Increased risk of lower-extremity amputation among Caucasian diabetic patients on dialysis.
      ] because of wound-healing impairment in patients with kidney disease [
      • Maroz N.
      • Simman R.
      Wound Healing in Patients With Impaired Kidney Function.
      ]. Early recognition of foot disease in these individuals is important to prevent consequent limb loss.
      Even under such poor circulation and high amputation risk scenarios, in the current study, a contiguous reduction of LEA rates over time was noted in DFD patients with ESRD. Particularly in major-LEA, there was a reduction from 13.67 % to 5.82 % for patients with ESRD that declined more obviously than patients without ESRD (3.48 % to 1.47 % respectively, P for interaction < 0.001). As per our speculation, the continual decrease of LEA rates in DFDs was mostly likely due to clinical awareness and more timely interventions, such as endovascular treatment [
      • Lin C.-W.
      • Armstrong D.G.
      • Lin C.-H.
      • Liu P.-H.
      • Hung S.-Y.
      • Lee S.-R.
      • et al.
      Nationwide trends in the epidemiology of diabetic foot complications and lower-extremity amputation over an 8-year period.
      ]. Of note, the performance of EVT in patients with DFDs and ESRD has increased dramatically nationwide, particularly in more recent years from 7.09 % of patients in 2004 to 29.41 % in 2017. Beyond the awareness of the importance of limb preservation, the high frequency of EVTs might also imply difficulty in treating patients with concomitant DFDs and ESRD because of the essentially severe peripheral atherosclerosis. Though not proof for causality, our study further documents that the trend of prominent rising rates of EVT in patients with ESRD is associated with concomitant decreasing major-LEA rates (P for interaction < 0.001). Accordingly, it would still be valid to perform EVTs aggressively for patients with ESRD for limb preservation [
      • Graziani L.
      • Silvestro A.
      • Bertone V.
      • Manara E.
      • Alicandri A.
      • Parrinello G.
      • et al.
      Percutaneous transluminal angioplasty is feasible and effective in patients on chronic dialysis with severe peripheral artery disease.
      ,
      • Kumada Y.
      • Aoyama T.
      • Ishii H.
      • Tanaka M.
      • Kawamura Y.
      • Takahashi H.
      • et al.
      Long-term outcome of percutaneous transluminal angioplasty in chronic haemodialysis patients with peripheral arterial disease.
      ].
      The lower prevalence of foot infection in patients with ESRD might have been underestimated, and foot infection sign in patients with ESRD might be hindered by limited inflammation response because of poor peripheral circulation and thus less immune cell reach and reaction [
      • Fry D.E.
      • Marek J.M.
      • Langsfeld M.
      Infection in the ischemic lower extremity.
      ]. Consequently, obscure symptoms or signs might lead to unawareness of mild foot infection such as cellulitis or abscess, particularly in patients with ESRD and PAD [
      • Lin C.W.
      • Yang H.M.
      • Hung S.Y.
      • Chen I.W.
      • Huang Y.Y.
      The analysis for time of referral to a medical center among patients with diabetic foot infection.
      ].
      According to our previous nationwide long-term diabetic foot study, promising trends of reducing gangrene on presentation paired with increases in vascular interventions suggest continued vigilance and rapid, coordinated interdisciplinary diabetic foot care in our country [
      • Lin C.-W.
      • Armstrong D.G.
      • Lin C.-H.
      • Liu P.-H.
      • Hung S.-Y.
      • Lee S.-R.
      • et al.
      Nationwide trends in the epidemiology of diabetic foot complications and lower-extremity amputation over an 8-year period.
      ]. In this study, we further noted a 4-fold increase of EVTs in the treatment of patients with both DFD and ESRD during the 14 years, which demonstrated the role of vascular specialists participating in the treatment of interdisciplinary teams. Though we found the decrease of major-LEA was associated with the performance of EVTs; nevertheless, it may not be possible to fully declare the contribution of other expertise from this claims data, such as the improvement of wound dressing, glycemic control, antibiotics, or surgical techniques.
      Several limitations should be considered here. The high prevalence of ESRD in Taiwan is based on increasing kidney replacement therapy access as in other countries with growing economies [
      • Thurlow J.S.
      • Joshi M.
      • Yan G.
      • Norris K.C.
      • Agodoa L.Y.
      • Yuan C.M.
      • et al.
      Global epidemiology of end-stage kidney disease and disparities in kidney replacement therapy.
      ]; consequently, we had the opportunity to explore the clinical characteristics of DFDs in patients with ESRD. It is notable that the trend of ESRD prevalence in patients with DFD and associated foot information in the current study might not apply globally. The current study used the Taiwan NHIRD to exemplify a population-level data source for generating real-world evidence. As with other claims databases, there have been some concerns about revalidation of the accuracy of diagnostic codes and issues around unmeasured confounders, as diagnostic codes cannot totally represent the disease condition, especially for detailed information like wound size, peripheral perfusion, or success rate of vascular interventions, and such information regarding the wound-healing process was mostly lacking from this claim data source. Furthermore, the conversion of coding measures from versions 9 to 10 since 2016 might have interfered with the consistency of diagnosis over the years. Nevertheless, we consider access and analysis of these grand trends according to such a nationwide database is valuable.

      5. Conclusions

      In conclusion, physicians should pay attention to the rising patient numbers with ESRD over these years with respect to the DFD issue. Patients with ESRD have accounted for more and more LEAs in this population that would be attributed to a high PAD ratio in ESRD. Fortunately, an apparent trend in lowering major-LEA was noted in patients with ESRD, which was associated with rising endovascular treatments. Certainly, the causal relationship between endovascular treatments and LEA rates as speculated from the statistical associations and the effect of the interdisciplinary team approach, particularly in vascular interventions for patients with DFD and ESRD, requires further prospective study design for validation.
      Ethics statement.
      The studies involving human participants were reviewed and approved by The Institutional Review Board of Chang Gung Memorial Hospital, Taiwan (No. 201801421A3C501). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.
      Funding.
      This study was supported by project grant from Chang Gung Memorial Hospital, Taiwan (Grant Number: CMRPG3L1221 and CMRPD1H0531). This study is partially supported by National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases Award Number 1R01124789-01A1.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Appendix A. Supplementary material

      The following are the Supplementary data to this article:

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