OBJECTIVETo determine whether dialysis treatment is an independent risk factor for foot ulceration in patients with diabetes and renal impairment.RESEARCH DESIGN AND METHODSWe performed a cross-sectional study of consecutive patients with diabetes and stage 4 or 5 chronic kidney disease (CKD) attending clinics in Manchester (U.K.). Patients were classified as either receiving dialysis therapy (dialysis) or not (no dialysis). Foot assessment included diabetic peripheral neuropathy (DPN), peripheral arterial disease (PAD), prior foot ulceration and amputation, and foot self-care. Risk factors for prevalent foot ulceration were assessed by logistic regression.RESULTSWe studied 326 patients with diabetes and CKD (mean age 64 years; 61% male; 78% type 2 diabetes; 11% prevalent foot ulceration). Compared with no dialysis patients, dialysis patients had a higher prevalence of DPN (79 vs. 65%), PAD (64 vs. 43%), prior amputations (15 vs. 6.4%), prior foot ulceration (32 vs. 20%), and prevalent foot ulceration (21 vs. 5%, all P < 0.05). In univariate analyses, foot ulceration was related to wearing bespoke footwear (odds ratio 5.6 [95% CI 2.5–13]) dialysis treatment (5.1 [2.3–11]), prior foot ulceration (4.8 [2.3–9.8], PAD (2.8 [1.3–6.0], and years of diabetes (1.0 [1.0–1.1], all P < 0.01). In multivariate logistic regression, only dialysis treatment (4.2 [1.7–10], P = 0.002) and prior foot ulceration (3.1 [1.3–7.1], P = 0.008) were associated with prevalent foot ulceration.CONCLUSIONSDialysis treatment was independently associated with foot ulceration. Guidelines should highlight dialysis as an important risk factor for foot ulceration requiring intensive foot care.

OBJECTIVETo identify factors that influence survival after diabetes-related amputations.RESEARCH DESIGN AND METHODSWe abstracted medical records of 1,043 hospitalized subjects with diabetes and a lower-extremity amputation from 1 January to 31 December 1993 in six metropolitan statistical areas in south Texas. We identified mortality in the 10-year period after amputation from death certificate data. Diabetes was verified using World Health Organization criteria. Amputations were identified by ICD-9-CM codes 84.11–84.18 and categorized as foot, below-knee amputation, and above-knee amputation and verified by reviewing medical records. We evaluated three levels of renal function: chronic kidney disease (CKD), hemodialysis, and no renal disease. We defined CKD based on a glomerular filtration rate <60 ml/min and hemodialysis from Current Procedural Terminology (CPT) codes (90921, 90925, 90935, and 90937). We used χ2 for trend and Cox regression analysis to evaluate risk factors for survival after amputation.RESULTSPatients with CKD and dialysis had more below-knee amputations and above-knee amputations than patients with no renal disease (P < 0.01). Survival was significantly higher in patients with no renal impairment (P < 0.01). The Cox regression indicated a 290% increase in hazard for death for dialysis treatment (hazard ratio [HR] 3.9, 95% CI 3.07–5.0) and a 46% increase for CKD (HR 1.46, 95% CI 1.21–1.77). Subjects with an above-knee amputation had a 167% increase in hazard (HR 2.67, 95% CI 2.14–3.34), and below-knee amputation patients had a 67% increase in hazard for death.CONCLUSIONSSurvival after amputation is lower in diabetic patients with CKD, dialysis, and high-level amputations.

OBJECTIVEThe receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) signaling pathway (RANKL/RANK/OPG signaling) is implicated in the osteolysis associated with diabetic Charcot neuroarthropathy (CN); however, the links with medial arterial calcification (MAC) seen in people with CN are unclear. This study aimed to investigate the role of RANKL/OPG in MAC in patients with CN.RESEARCH DESIGN AND METHODSEnzyme-linked immunosorbent assay and Bio-plex multiarray technology were used to quantify a range of cytokines, including RANKL and OPG in sera from 10 patients with diabetes, 12 patients with CN, and 5 healthy volunteers. Human tibial artery segments were immunohistochemically stained with Alizarin red and human RANKL antibody. Human vascular smooth muscle cells (VSMCs) were also explanted from arterial segments for in vitro studies.RESULTSWe demonstrate colocalization and upregulation of RANKL expression in areas displaying MAC. Systemic levels of RANKL, OPG, and inflammatory cytokines (interleukin-8, granulocyte colony–stimulating factor) were elevated in those with CN compared with diabetic patients and healthy control subjects. Human VSMCs cultured in CN serum showed accelerated osteoblastic differentiation (alkaline phosphatase activity) and mineralization (alizarin red staining) compared with cells treated with diabetic or control serum (P < 0.05). Coincubation with OPG, the decoy receptor for RANKL, attenuated osteogenic differentiation of VSMCs and was independent of a high calcium-phosphate milieu. The accelerated mineralization induced by RANKL and CN serum correlated with nuclear translocation of nuclear factor-κB, a process abrogated by OPG.CONCLUSIONSOur data provide direct evidence that RANKL/RANK/OPG signaling is modulated in patients with CN and plays a role in vascular calcification. This study highlights this pathway as a potential target for intervention.

OBJECTIVETo evaluate the prevalence of lower-limb complications in a multiracial cohort of patients with diabetes receiving dialysis.RESEARCH DESIGN AND METHODSThis work was a cross-sectional study of lower-limb complications in dialysis-treated patients with diabetes in the U.K. and U.S.RESULTSWe studied 466 patients (139 U.K.; 327 U.S.). The prevalence of lower-limb complications was high (foot ulcers 12%, neuropathy 79%, peripheral arterial disease 57%, history of foot ulceration 34%, and prior amputation 18%), with no significant ethnic variation, except that foot ulcers were more common in whites than in patients of African descent (P = 0.013). Ninety-five percent of patients were at high risk of lower-limb complications. Prior amputation was related to foot ulcer history, peripheral arterial disease, and hemodialysis modality in multivariable analysis. Prevalent ulceration showed independent associations with foot ulcer history and peripheral arterial disease, but not with ethnicity.CONCLUSIONSAll patients with diabetes receiving dialysis are at high risk of lower-limb complications independent of ethnic background.

Among the spectrum of risk for diabetic foot disease conferred by chronic kidney disease (CKD), end-stage renal disease (ESRD) has emerged as a novel independent risk factor. Apart from the classical triad of neuropathy, infection, and peripheral arterial disease that operate in these individuals, the risk is further compounded by inadequate foot self-care by patients and by dialysis centers not providing onsite foot care, as medical priorities are diverted to the dialysis itself. Consequently, the burden of diabetic foot disease has increased in the CKD and ESRD population as exemplified by high ulceration, amputation, and foot-related mortality rates. Current guidelines on foot care in diabetes should recognize advanced CKD and ESRD/dialysis as a separate risk factor for foot disease to alert professionals and highlight the opportunity for prevention. Recent studies have demonstrated improved foot outcomes when chiropody programs are instituted within dialysis units.

Although neuropathic ulceration remains the commonest type of foot ulcers among patients with diabetes, recent data suggest that ischemic (and therefore, neuroischemic) ulcers are on the rise. The high prevalence and incidence of diabetes and its attendant foot complications, coupled with the current trend where increasingly diabetes care is being provided by general practitioners (primary care physicians) would mean that primary care practices are expected to see greater numbers of diabetic foot ulcer patients. Unfortunately, these settings are frequently ill-equipped to appropriately manage diabetic foot ulcers either due to lack of adequately trained personnel and access to multidisciplinary foot care teams. Whereas neuropathic foot ulceration may appear to be less challenging, neuroischemic or ischemic ulcers portend a higher risk of adverse outcomes, including non-healing, infection, amputation, and death. The last 2 decades have witnessed a paradigm shift from neuropathy as the main etiological factor in diabetic foot disease to an ever-increasing preponderance of ischemic and/or neuroischemic ulceration. Available literature does not always consider the limited access primary care practices have to specialized multidisciplinary foot care teams. Additionally, in the case of neuroischemic and/or ischemic ulcers, existing guidelines on their diagnosis and management are varied and unclear. This review aimed at providing a simple understanding to the complex evidence base for diagnosing and treating neuroischemic and/or ischemic ulcers in a primary care setting. It emphasizes the need for urgent vascular review in all patients with ischemic/ neuroischemic ulcers and advocates effective participation of vascular specialists in diabetic foot clinics and combined ward rounds.

Patients with diabetes have increased risk for foot ulcers, amputations and hospitalisations. We evaluated a closed cohort of patients with diabetes and established risk factors in two high risk groups: (i) dialysis patients and (ii) patients with previous foot ulceration. We used claims data for diabetes (ICD-9 250.X), ulceration (ICD-9 707·10, 707·14 and 707·15) and dialysis (CPT 90935-90937) from the Scott and White Health Plan to identify 150 consecutive patients with diabetes on dialysis (dialysis group) and 150 patients with a history of foot ulceration (ulcer history group). We verified these diagnoses by manually reviewing corresponding electronic medical records. Each patient was provided 30 months follow-up period. The incidence of foot ulcers was the same in dialysis patients and patients with an ulcer history (210 per 1000 person-years). The amputation incidence rate was higher in dialysis patients (58·0 versus 13·3, P < 0·001). Hospital admission was common in both study groups. The incidence of hospitalisation was higher in the ulcer history group (477·3 versus 381·3, P < 0·001); however, there were more foot-related hospital admissions in the dialysis group (32·9% versus 14·0%, P < 0·001) during the 30-month evaluation period. The incidence of ulcers, amputations and all-cause hospitalisations is high in persons with diabetes and a history of foot ulceration or on dialysis treatment; however, those on dialysis treatment have disproportionately higher rates of foot-related hospitalisations. Intervention strategies to reduce the burden of diabetic foot disease must target dialysis patients as a high-risk group.

Type 2 diabetes is associated with increased cardiovascular morbidity and mortality and early vascular ageing. This takes the form of atherosclerosis, with progressive vascular calcification being a major complication in the pathogenesis of this disease. Current research and drug targets in diabetes have hitherto focused on atherosclerosis, but vascular calcification is now recognised as an independent predictor of cardiovascular morbidity and mortality. An emerging regulatory pathway for vascular calcification in diabetes involves the receptor activator for nuclear factor κB (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG). Important novel biomarkers of calcification are related to levels of glycation and inflammation in diabetes. Several therapeutic strategies could have advantageous effects on the vasculature in patients with diabetes, including targeting the RANKL and receptor for AGE (RAGE) signalling pathways, since there has been little success-at least in macrovascular outcomes-with conventional glucose-lowering therapy. There is substantial and relevant clinical and basic science evidence to suggest that modulating RANKL-RANK-OPG signalling, RAGE signalling and the associated proinflammatory milieu alters the natural course of cardiovascular complications and outcomes in people with diabetes. However, further research is critically needed to understand the precise mechanisms underpinning these pathways, in order to translate the anti-calcification strategies into patient benefit.