Association between Diabetic Kidney Disease and Diabetic Foot Ulceration

Abstract

Diabetic kidney disease (DKD) is a common global health challenge characterized by a decline in renal function among the diabetic population, which progresses to end-stage renal disease (ESRD). Evidence in the literature suggests a strong association between DKD and the development of diabetic foot ulceration (DFU). DFU is a serious health issue that complicates both type 1 and type 2 diabetes mellitus, and negatively impacts the quality of life of diabetic patients. Patients with advanced DKD or ESRD have a five-fold increased risk of developing DFU, with 6.5–10 times higher rate of amputation than their non-nephropathic counterparts. Multiple and inter-related pathways of DFU in DKD have been identified in which ischemia, neuropathy and infection are major contributing pathologies. However, extensive research to comprehensively assess the progression of DFU in DKD is lacking. In this chapter, we discuss the causal pathways in DFU development and progression, the relationship between DKD and DFU as well as treatment options and measures to achieve both primary and secondary prevention.

1. Introduction

Diabetic foot ulceration (DFU) is a serious complication of diabetes mellitus worldwide, and the most common cause of in-patient admissions among the diabetic population [1, 2]. It reduces mobility and quality of life of patients. Left untreated or poorly managed, DFU can lead to amputation, and death in extreme cases [3]. The etiology of DFU is quite complex due to the involvement of a number of pathophysiological mechanisms, with polyneuropathy being the most crucial of them all [4, 5]. Proper adherence to standard treatment strategies (both pharmacological and non-pharmacological) and interdisciplinary cooperation between healthcare practitioners (doctors, nurses, pharmacists, etc.) and the patient can reduce the relatively high rates of major amputations and mortality in diabetic patients due to DFU [6, 7, 8].

Diabetes-related foot complications have been identified as the most common cause of morbidity among diabetic patients [1]. Peripheral vascular disease is a major underlying risk factor for the development of DFU due to reduced oxygenation of the foot. It renders the diabetic foot asymptomatic until latter evidence of non-healing ulcers become evident [9, 10]. Also, uremia due to diabetic kidney disease (DKD) reduces the body’s immune capabilities and creates a suitable environment for bacterial growth in the foot ulcers [11]. Inadequate oxygenation or perfusion of the affected foot aids in the progression of DFU due to a reduced delivery of antibiotics to the affected foot. At this point, the patient needs to be monitored strictly to prevent the steady progression of DFU to diabetic gangrene, a condition where foot ulcerations become necrotic and unresponsive to antibiotic therapy and ultimately may require amputation of the affected foot [12, 13].

While about 6.3% of patients currently have foot ulcerations worldwide [14], it is estimated that about 25% of diabetic patients may develop DFU in their lifetime [5]. Of all amputations in diabetic patients, 85% are preceded by DFU, which subsequently worsens to a gangrene or infection [3, 15]. DFU is more prevalent in type 2 diabetic patients, with these patients suffering recurring hospital admissions which increases their financial burden on the healthcare system and the patient [16]. Everett and Mathioudakis [17] recently reported that diabetic patients with DFU have 2.5 times increase of dying while experiencing an 11-fold increase in hospital costs compared to patients hospitalized for nondiabetic foot ulcer. A patient’s likelihood of developing DFU increases as his or her disease duration increases [18], while complications such as DKD further increases the patient’s risk of getting foot ulcers [19]. Furthermore, the severity of DFU delays wound healing time [18, 20], which consequently increases the cost of its clinical management. This chapter discusses the causal pathways in DFU development and progression, the relationship between DKD and DFU as well as treatment options and measures to achieve both primary and secondary prevention.

2. Pathophysiology of diabetic foot ulceration

DFU is a complex condition which has a host of pathological mechanisms involved in its development and progression. Thus, multiple and inter-related pathways of DFU have been identified in which diabetic peripheral neuropathy, peripheral vascular disease and ischemia, and infection are major contributing pathologies [21, 22, 23].

2.1 Diabetic peripheral neuropathy

Diabetic peripheral neuropathy (DPN) is considered the cardinal driving force to developing DFU. It is a condition where nerves in the limbs (lower limbs in the case of DFU) are damaged by a variety of conditions such as inflammation, oxidative stress, advanced glycated end-products and a decrease in nitric oxide production [24, 25, 26]. The nerve damage renders the diabetic feet insensitive to harmful stimuli such as trauma from stepping on a hot or sharp object or skin injury from wearing ill-fitted shoes. It is reported that over 60% of foot ulcers among the diabetic population is directly linked to the development of DPN [24, 25, 26]. An increased activity of aldose reductase and sorbitol dehydrogenase (enzymes involved in the alternate metabolism of glucose under hyperglycemic conditions) leads to the accumulation of sorbitol and fructose [27]. High concentrations of these sugars negatively impact the levels of myoinositol, a carbocyclic sugar that mediates cell signal transduction in response to neurotransmitter and hormones [28, 29]. In DPN, there is reduced nerve innervation of small muscles of the foot as well as a decline in peripheral sensation and vasomotor control of the pedal circulation. This leads to development of wounds in these patients, which progress to ulcers that go unnoticed until observed by someone else [30].Diabetes mellitus also promotes skin fissuring and dryness (reduced sweating), a situation which makes the skin prone to infections (due to the cracks in the skin acting as a potential portal for entry of bacteria) and poses as a risk factor in the expansion and worsening of DFU [31, 32].DPN may reduce the production of neuropeptides such as substance P, calcitonin gene-related peptide and nerve growth factor, as these neuropeptides are important for wound healing [33, 34, 35]. These changes aid the progression of wounds and ulcers to gangrenes, coupled untimely management (with pharmacological or surgical intervention) ultimately leads to the loss of a limb. Also, the lack of pain sensation exposes the feet of diabetic patients with sensory neuropathy to repeated unnoticed trauma. It is important to note that the lack of pain sensation and impaired temperature sensation, both being components of sensory neuropathy, can make the instant withdrawal of a foot from harmful objects or hot liquid impossible [36, 37]. This creates an ulcer which may become chronic due to constant exposure to obnoxious stimuli. Furthermore, repeated pressure at focal point within the foot leads to the development of foot ulcers. This is partly linked to flexor extension imbalance and muscle atrophy, which develops in some diabetic patients, causing unequal distribution pressure and prominence of the diabetic foot [38, 39]. Thus, DPN creates repeated and unequal distribution pressure in the feet of diabetic patients, leading to development of DFU.

2.2 Peripheral vascular disease and ischemia

Hypoperfusion (ischemia) resulting from peripheral vascular disease contributes to DFU development due to reduced oxygen supply to the diabetic foot [40]. The vascular disease in diabetic patients is mostly localized in arteries of the lower limb, with dismal prognosis [41, 42]. A major risk factor for the development of peripheral vascular disease is atherosclerosis [43, 44], a condition in which an artery become hardened or thickened due to a buildup of plaque in its inner lining. Atherosclerosis appears at a younger age in diabetic individuals and progresses more rapidly than in nondiabetic individuals [45, 46], thus making diabetes mellitus one of the risk factors for developing atherosclerosis. In the diabetic microcirculation, there is existence of structural changes, most notably, a thickening of the capillary basement membrane and endothelial dysfunction [47, 48]. As already mentioned, DPN reduces the production of neuropeptides which aid in wound healing [33, 34, 35]. These neuropeptides directly and indirectly (through mast cell release of histamine) cause increased permeability and vasodilation [49, 50]. The endothelium plays an important role in blood vessel wall function by synthesizing and releasing vasodilators such as prostaglandins and nitric oxide, which modulate vascular tone in pedal circulation [51, 52]. A host of mechanisms responsible for vascular dysfunction in diabetes have been identified to include over-production of reactive oxygen species, impaired nitric oxide pathway, abnormal production of vasoconstrictor prostanoids, intracellular signaling and advanced glycated end products [53, 54, 55]. This pathological vascular alteration in the diabetic foot contributes to DFU development, suggesting that diabetic patients must undergo a timely vascular examination for timely revascularization.

2.3 Infection

The immune system of healthy people is much more robust and stronger than that of diabetic individuals [56, 57] and thus, foot infections in the latter group need to be closely monitored and managed appropriately [58, 59]. Unsurprisingly, it is estimated that about 50% of patients with DFU present clinical signs of infection (either locally or systemically) [60, 61]. A foot infection is characterized by the presence of purulent secretions or at least two of the classic signs of inflammation (erythema, hyperemia, edema, or swelling and pain) [62, 63]. Patients with poor metabolic or uncontrolled diabetes are commonly afflicted with bacterial infection in which a lack of granulation tissue, delayed healing, appearance of necrotic tissue on wound surface and/or odor are prominent [64, 65]. Furthermore, these patients display a loss of sensitivity (i.e. diabetic peripheral neuropathy) in the affected foot due to damage caused to short and long fibers (A-beta and A-delta) secondary to hyperglycemia [66, 67]. Chronic hyperglycemia, a hallmark of diabetes mellitus, provides a suitable medium for bacterial growth, mainly aerobic Gram-positive cocci (e.g. Staphylococcus aureus), Gram-negative aerobes (e.g. Pseudomonas aeruginosa) and drug-resistant bacteria such as vancomycin-resistant S. aureus and methicillin-resistant S. aureus, which were the common microorganisms identified in the diabetic foot [68, 69, 70]. In extreme situations, the bacterial infection of soft tissue spreads to the bones (causing osteomyelitis; an inflammation in the bone) and other surrounding tissues and organs. Unsuccessful attempts at halting the spread of the infection may lead to septicemia and amputation of the affected limb [65, 70]. Also, uncontrolled diabetes mellitus impairs the proliferation of fibroblasts and collagen synthesis while prolonging an inflammatory cascade [71, 72], a condition which compromises the wound healing abilities of diabetic patients. In summary, persistent hyperglycemia in diabetic individuals creates a suitable microenvironment for the growth of pathogenic bacteria, which contributes to DFU development and progression.

3. Renal involvement in diabetic foot ulceration

3.1 Diabetic patients with chronic kidney disease and end-stage renal disease

Chronic kidney disease (CKD) is clinically defined by the presence of persistent albuminuria (albumin-to-creatinine ratio ≥ 30 mg/g for at least 3 months) regardless of etiology [73, 74]. It is estimated that about 40% of patients with DKD are expected to develop CKD at a point in their life [75]. The progression of CKD to end-stage renal disease (ESRD; the final stage of CKD) is higher in diabetic patients compared to their nondiabetic counterpart, so as is the mortality rate of these patients with DFU [76]. Calciphylaxis, uremic pruritus and nephrogenic systemic fibrosis are skin disorders that increase the risk of DFU development in patients with DKD [77, 78, 79]. Calciphylaxis, for example, presents with painful skin lesions which progress into a necrotic nonhealing skin ulcer and occasionally, gangrene in ESRD patients. It is a rare and life-threatening complication in which calcium accumulates in small blood vessels of the skin, occurring in about 1% of ESRD patients annually [78, 80]. Although its exact pathophysiology remains unclear, some studies suggest that abnormal bone and mineral metabolism, hyperparathyroidism, and vitamin D therapy contribute to the development of this disorder [81, 82]. Given that the most common clinical presentation of calciphylaxis is nonhealing lower extremity ulcers, its timely identification by relevant healthcare professionals is critical [83, 84].

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, 101, 102, 103, 104, 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, 107, 108, 109, 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.

3.2 Diabetic patients on renal dialysis

Another group of diabetic patients in which the kidney contributes to DFU development or progression are those receiving dialysis therapy. Dialysis patients who have markedly higher risks of DFU or amputation include those with previous foot ulceration or amputation, diabetes mellitus, DPN, or macrovascular disease [115, 116]. Other studies also found that reduced mobility and dexterity due to dialysis may impair the patient’s ability to perform foot inspection or foot self-care. In addition, prolonged periods of inactivity on a dialysis couch for at least three times in a week could further contribute or worsen DFU by enhancing the development of pressure ulcers (prolonged pressure-induced skin injury) [117]. A retrospective study of 90 diabetic patients on dialysis therapy showed a high incidence of DFU and amputation before the start of dialysis, with a further increase following 2 years after dialysis initiation [115]. Therefore, it can be inferred that the dialysis treatment was a driving force in DFU progression and its complications. Such a negative effect of dialysis on DFU was later supported by the findings from a multiethnic study in which 400 diabetic patients on dialysis were reported to be at high risk for foot complications [118]. This finding was confirmed in another study by the same authors in which dialysis independently increased the risk for DFU in 137 diabetic patients, with an odd ration of 4.2 after including diabetic neuropathy, peripheral vascular disease, foot self-care measures and other potential confounders [119]. Miyajima et al. [102] also observed that major amputation rates are markedly increased in diabetic patients undergoing hemodialysis, with dismal prognosis while only half of diabetic patients on dialysis avoided major amputation regardless of revascularization [103]. In another study, amputation rate was reported to be 57% among diabetic patients receiving hemodialysis while 25% was reported in their counterparts with pre-dialysis ESRD [96]. In the same vein, diabetic patients on dialysis with critical foot ischemia had 8.9 times increased risk of poor prognosis [120].

McGrath and associate [121] also studied a close relationship between the time of dialysis initiation and development of diabetic foot complications. In a majority of diabetic patients, they found that the period from commencement of dialysis to amputation was less than 1 year, with the median being 7 months. Their observation was later corroborated by the findings of Game et al. [115] who reported a significant increase in the rate DFU onset by 3.3 (95% CI, 1.59–7.04) in the first year after commencement of dialysis while that between the second and fifth years increased by 4.56 (95% CI, 2.19–9.50). In the same study, the authors further reported that the increases in the incidence of major amputation were 31.98 (95% CI, 2.09–490.3) and 34.01 (95% CI, 1.74–666.2) in the first year and second to fifty year of dialysis respectively [115]. Similarly, compared to the general diabetic population, a 10-times increase in nontraumatic amputation rate was reported, as seen in 11.8–13.8/100 person-years in diabetic patients on dialysis [98], while diabetes mellitus was identified as the main risk factor for amputation of lower limb among patients on hemodialysis [122]. Tragically, the rates of mortality among amputees receiving dialysis therapy are disproportionately high regardless of successful post-amputation rehabilitation. For example, 50% mortality was reported within 1 year in 14 diabetic patients receiving dialysis therapy compared to 33% 1-year mortality rate in diabetic patients receiving treatment for heart failure [123]. Also, a study involving a large cohort of diabetic patients revealed increased post-amputation mortality rates, which corresponded with worsening renal condition, with dialysis patients being the most affected [124]. As infection (or sepsis) is a principal aggravating factor in DFU development and progression, it has been identified as a contributing factor next to cardiovascular disease in the mortality of diabetic patients on dialysis. A case-control study that sought to investigate the rates of mortality following diabetes-associated amputation revealed sepsis as a major cause of post-amputation mortality (49% of cases) compared to mortality due to heart-related diseases (45%) [125]. Although the authors did not include diabetic patients receiving dialysis therapy in their study, the implication of their findings is very important, as diabetic patients receiving dialysis treatment are easily vulnerable to infection. On a whole, dialysis increases the rate of DFU onset and progression as well as lower limb amputation and post-amputation mortality.

3.3 Renal transplantation in diabetic patients

There is limited data to the contribution of kidney transplantation on the onset and progression of DFU. However, it is well-known that as a result of induction and maintenance of immunosuppression in kidney transplant recipients, they represent a special group that is highly susceptible to infection. Diabetic patients in this group may develop DFU from opportunistic infections which require hospital admissions because these infections are difficult to treat. Moreover, their compromised immune system due to immunosuppressive therapy may impair wound healing. Such a condition may lead to septicemia which can progress to sepsis [126]. There are studies showing amputation rates as high as 30% in this group of patients [126, 127, 128]. It is important to note that peripheral vascular disease is common among renal transplant recipients [127, 129], which increases their risk for DFU development. In the light of this, Sharma et al. [130] recently reported that about 1 in 7 patients develop a new onset DFU following kidney transplantation or simultaneous pancreas-kidney transplantation although glycemic status is well-controlled. They also observed that DFU increases the risk of failure of the renal graft [130]. Although data regarding the effect of kidney transplantation on DFU development and progression are scarce, the few studies done so far suggest that kidney transplantation increases the risk of developing DFU.

4. Current treatment options and prevention

The management of DFU involves pharmacological, non-pharmacological approaches and/or surgery. A patient’s suitability for each management option depends on factors such as state of the wound (non-infected, necrotic or gangrenous), required frequency for assessment, and the likelihood for patient compliance (mobility and financial capabilities).

4.1 Pharmacological approach

The selection of appropriate treatments should be based on the results of a wound culture once an infection is suspected. For accurate results during wound culture, it is ideal to harness tissue from the base of the ulcer after debridement rather than taken from a superficial wound [131, 132]. If deep tissue infections are suspected, specimens obtained aseptically during surgery provide optimal results. Chronic or previously treated wounds most often show polymicrobial growth, including Gram-positive cocci, Gram-negative rods or anaerobes and fungi in some cases [133]. Antibiotic-resistant organisms such as vancomycin-resistant S. aureus and methicillin-resistant S. aureus are frequently found in patients previously treated with antibiotic therapy or patients with a recent history of hospitalization or residence in a long-term care facility [134, 135]. The selection of appropriate antimicrobial therapy, including the agent, route of administration, and need for inpatient or outpatient treatment will be determined in part by the severity of the infection. In-patient admissions should be offered to individuals with systemic signs of severe infection with the provision of supportive care and intravenous antibiotic therapy based on result obtained from wound culture [136, 137]. Common classes of pharmacological agents used include lincosamides, fluoroquinolones, β-lactams/β-lactamase inhibitors [138, 139], and exogenous sources of agents such as nitric oxide that stimulate angiogenesis and vasodilation.

4.2 Non-pharmacological approach

4.2.1 Debridement

Debridement is one of the cornerstones of wound management, which could be surgical or non-surgical. It involves removal of necrotic tissue to aid wound healing. Debridement of open foot ulcers is required if unhealthy tissue is present, as this will aid in decreasing pressure points at callused sites on the foot [140, 141]. Removal of unhealthy tissue is linked to reducing colonizing a “clean” wound and allowing for examination of deep-lying tissues in the ulcer. Wound dressing is the cornerstone in diabetic foot care. As a convention, dressing changes and wound inspection and dressing should be done daily or as determined by the physician [142]. An ideal dressing should contribute to a moist wound environment, absorb excessive exudates, and not increase the risk for infections. Luckily, some non-surgical debriding agents have been incorporated with biologics such as transforming growth factor-β, vascular endothelial growth factor and epidermal growth factor [142, 143, 144]. Compared to conventional wound dressings, this modern wound dressing technique hastens the process of wound healing, as it stimulates angiogenesis, fibroblast proliferation, collagen synthesis and deposition, epithelization and remodeling of new extracellular matrix.

4.2.2 Surgery

Surgical management is considered an integral part of diabetic foot care, which is based on recent advances in technology and comprehensive understanding of the pathophysiology underlying DFU. Bypass surgery is a common method of treatment for ischemic limbs to preserve the functional anatomy of the diabetic foot. In cases where there are multiple levels of occlusion, surgery allows revascularization to restore arterial blood flow and increase the chance for limb salvage [145]. Prior to surgery, the possibility of underlying osteomyelitis should be considered with the presence of exposed bone [146]. The patient may undergo surgical excision of the affected bone or an extensive course of antibiotic therapy if septicemia is suspected [147].

4.3 Prevention of diabetic foot ulceration in patients with diabetic kidney disease

As DFU and its complications in patients with DKD either pre-, intra- or post-dialysis increases morbidity, mortality and financial burden, its prevention has become imperative. Unfortunately, foot care or chiropody programs have not been established in dialysis centers globally. This is a worrying picture, especially among patients with the highest risk of developing DFU. This group of patients include dialysis patients, amputees and those with history of foot ulceration. Emerging evidence shows that establishment of chiropody programs at dialysis units presents several benefits such as significant drop in the incidence of DFU among amputees and dialysis patients as well as reduction in the incidence of amputations, and improvement in ulcer healing times in the period when education on foot care and assessment, and provision of therapeutic shoes were introduced [148, 149, 150, 151]. The beneficial outcomes of these preliminary studies suggest that instituting chiropody programs at all dialysis centers led by dialysis nurses would greatly reduce the burden of DFU and its complications on dialysis patients, healthcare system and society.

5. Conclusion

DFU is a common complication in diabetic patients, and remains a major cause of morbidity in patients with DKD. It has a complex pathophysiology involving a host of metabolic and hemodynamic processes such as diabetic peripheral neuropathy, ischemia (due to diabetic vascular disease) and infections. DFU deteriorates into gangrenes and necrotic wounds when left untreated or when not adequately attended to. Due to its complexity, a team of healthcare professionals are needed in the management of foot ulcerations involving both pharmacological and non-pharmacological interventions to address all three contributing pathologies (neuropathy, ischemia and infection). In some extraordinary cases, surgery maybe needed to provide revascularization, off-loading to relieve high-pressure areas and ultimately relief to patients. As there is significant renal contribution to DFU development and progression, preventive measures should include the need to institute chiropody programs at all dialysis centers to reduce the burden of DFU on dialysis patients, healthcare system and society.