*Association between Diabetic Kidney Disease and Diabetic Foot Ulceration DOI: http://dx.doi.org/10.5772/intechopen.107825*

As diabetic peripheral neuropathy is one of the major contributing factors in DFU development and progression, uremic neuropathy, a sensorimotor neuropathy caused by uremic toxins, is a common complication of ESRD in which glomerular filtration rate (GFR) of the patient is <12 mL/min due to a buildup of dialyzable neurotoxins [85, 86]. The coexistence of uremic neuropathy and diabetes mellitus suggests that the clinical manifestations of diabetic neuropathy overlap with uremic neuropathy in diabetic patients with CKD and/or ESRD. Diabetic patients with ESRD also show immune vulnerability to infections, as hyperglycemia creates a veritable medium for bacterial growth and infection. As such, infections account for the second cause of mortality next to cardiovascular etiologies among diabetic patients with ESRD, representing 20% of the death of these patients, and also contributes significantly to their morbidity partly due to a decreased bactericidal activity of neutrophils [87, 88]. Moreover, pathological changes in complement function and significantly elevated levels of pro-inflammatory cytokines were associated with reduced renal clearance and persistent infection in diabetic patients with ESRD [89, 90].

In addition to uremic neuropathy and infection in diabetic patients, peripheral vascular disease was also found to increase the progression and severity of DFU, with an incidence rate in patients with CKD stage 1, 2 and 3 or 4 to be 4.7, 4.9 and 8.6 respectively [91, 92]. Of note, the risk factors for DFU can be seen in all stages of CKD, with microalbuminuria (the major clinical feature of DKD) as an independent risk factor for DFU [93]. Interestingly, Margolis et al. [94] found that the hazards of DFU increased by twofold and threefold in patients with CKD stage 3 and 4 respectively, while the risk for DFU decreased with improvement in renal function. ESRD, the final stage of CKD, increases the frequency of DFU and other foot complications such as infection, gangrene and amputation, with a twofold increase in diabetic patients relative to their non-ESRD counterparts [95, 96]. A previous study involving a cross-sectional examination of diabetic patients with and without ESRD also showed a fourfold increased risk of DFU complication among those with ESRD compared to their non-nephropathic diabetic counterparts [95]. These reports were later supported by the findings of Wolf and colleagues [97], who also observed that every 10 mL/min increase in estimated GFR (eGFR; a test of renal function and stage of CKD) corresponded with a 30% and 13% decrease in the odds of developing DFU in type 1 and type 2 diabetic patients respectively. As ESRD is associated with increase in diabetic foot complications such as amputation, a substantial body of evidence shows that amputation rate among diabetic patients with ESRD is 6.5–10 times higher compared to non-nephropathic diabetic population [96, 98, 99], with a low chance of diabetic wound healing as well as failure of healing from transmetatarsal amputations [100–105]. Also, a retrospective study of the effect of renal function on the development, severity, and outcome of DFU shows that reduced creatinine clearance increases the risk for DFU, with peripheral neuropathy and peripheral vascular disease also associated with DFU development [100].

Worsening the situation in diabetic patients with ESRD is the fact that tissue oxygenation is reduced as a result of decreased synthesis and release of erythropoietin (a hormone of renal origin which stimulates red blood cell production), culminating in anemia of ESRD, and thereby impairing diabetic wound healing [106–110]. Also, iron replacement therapy used by ESRD patients in the management of anemia has been recently shown to delay wound healing in these patients [111]. This is because iron inhibits cofactor p300, needed for the synthesis and release of vascular endothelial growth factor (VEGF) by hypoxia inducible growth factor-1α [111]. VEGF regulates and maintains angiogenesis (a physiological process through which new blood vessels form from pre-existing vessels) [112, 113]. Results from recent preclinical studies suggest that iron depletion with deferoxamine (a heavy metal chelator) in rats improves tissue oxygenation and facilitates wound healing by curtailing iron-mediated impairment of VEGF upregulation [114]. Taken together, these findings imply that the range of DKD from microalbuminuria to ESRD represent a chain of risk factors for DFU development and progression.
