Understanding The Impact Of End-Stage Renal Disease On Healing In Patients With Diabetes
End-stage renal disease (ESRD) can have devastating effects on patients with diabetes, including peripheral arterial disease, calciphylaxis and the need for dialysis. These authors offer insights on which complications to be vigilant for in patients with ESRD and discuss key considerations in developing appropriate treatment plans.
The effects of diabetes on ulcerations are well established as are the multitude of complications that may arise from diabetic foot ulcers. Consequently, researchers are rapidly recognizing the impact of end-stage renal disease (ESRD) on ulcerations. One of the complications of diabetes is nephropathy as 25 to 30 percent of all patients with diabetes develop kidney damage secondary to meager glycemic control and arterial hypertension.1-2
From the onset diagnosis of diabetes mellitus, an estimated 4 to 17 percent of patients will experience ESRD at 20 years out and 16 percent will have ESRD at 30 years out, making diabetic nephropathy the most common cause and primary etiology of ESRD.3-4 In 2010, the United States Renal Data System calculated diabetes to be the precipitating factor for ESRD in 45 percent of patients.5 With medical advancements and the increased lifespans of patients with diabetes, more patients are living long enough to develop ESRD, making it imperative to understand its effects on limb salvage.
Key Insights On The Effects Of ESRD On Patients With Diabetes
It is important to note that while diabetes is a source for pedal ulcerations, ESRD is an independent risk factor for developing wounds in patients with diabetes. Studies have shown a positive correlation between the risk of foot ulcerations and the severity of renal impairment.6
With ESRD being defined as an irreversible renal failure that requires renal replacement therapy (dialysis), Ndip and colleagues conducted a study specifically observing dialysis as an independent risk factor for foot ulcerations.7 The authors concluded that foot ulcerations were five times more likely in patients with diabetes receiving dialysis than patients with diabetes who have chronic kidney disease but are not yet on dialysis. Not only did they prove that dialysis is an independent risk factor for ulceration, Ndip and coworkers also observed a twofold increase in the prevalence of other lower extremity complications such as peripheral arterial disease (PAD) and amputations in dialysis-treated patients. It is important to note that while the authors adjusted this increase in lower extremity complications in their multivariable model to define the relationship between dialysis and foot ulcerations, the study’s complication rate results advance the investigation of the effect of ESRD on limb salvage.
Limb salvage is the primary objective of physicians treating patients with diabetic ulcerations. However, Hill and coworkers not only found an increase in foot ulcerations in patients with ESRD, they also found a fourfold increase in diabetic foot complications, defined as infection, gangrene and amputation.8
Unfortunately, multiple studies have also drawn the same conclusions regarding increased amputation rates in dialysis patients. Studies by McGrath and Curran as well as Morbach and colleagues found an increase in amputation rates for patients on dialysis in comparison to patients with diabetes with chronic kidney disease alone.9-10 McGrath and Curran specifically found the median time for amputation to be seven months after starting dialysis.9
However, there is a lack of evidence defining the primary cause of amputation in this specific patient population. Is it indeed the “seven-month duration” of ESRD (dialysis) or is the observed concurrent increase in PAD prevalence associated with ESRD the primary cause of amputation? Further, what is the optimal treatment for these patients? These are important topics to investigate as studies have shown that following amputation, there is a 35 percent increase in the one-year mortality rate in patients with ERSD in comparison to patients with diabetes without kidney impairment.11
Essential Considerations And Complications In Patients With ESRD
This presented data regarding ESRD and its lower extremity complications validates the need for physicians to have an even higher level of suspicion for diabetic foot complications. In order to do so, it is imperative to understand the pathophysiological effects ESRD has on ulcerations and wound healing. End-stage renal disease is multifactorial and incites ulcerations and delays in wound healing in a combination of processes.
Peripheral arterial disease. Adequate blood supply is crucial for wound healing. Currently one-quarter of adults on hemodialysis have PAD.12–14 Kidney disease not only singlehandedly increases the incidence of PAD threefold in comparison to patients without renal disease but the severity of PAD worsens as kidney disease progresses.12-14 Kidney disease alone is not the only aggravating factor for PAD. The coexistence of ESRD and diabetes further exacerbates PAD, increasing the number of adults with PAD to one in three.13-14 Authors have attributed this vascular morbidity not only to atherosclerosis but the accelerated calcification of vessels.13-14
Two synergistic complications of ESRD drive calcification of the vessels. First, diminished kidney function inhibits the clearance of phosphate-generating hyperphosphatemia, which disrupts the calcium phosphate solubility product by exceeding extracellular concentrations and inducing calcium and phosphate deposits into vessels.15 The other complication is secondary hyperparathyroidism. The parathyroid hormone operates to increase and maintain blood calcium levels. Therefore, an increase in parathyroid hormone synergistically provokes the increased calcium-phosphate extracellular concentration, further driving calcification and advancing PAD.16-18
Calciphylaxis. Calciphylaxis is a potential ramification of PAD in patients with ESRD. It is a thrombolytic event that provokes ischemia and tissue infarction. The lower extremities are the most commonly areas involved with calciphylaxis.19 Lesions begin with painful red areas that develop into indurated plaques followed by eschar, ulceration and gangrene. The cause of the thrombolytic event in calcified vessels is not known but the one-year mortality rate for those diagnosed with calciphylaxis is greater than 50 percent, and is most often secondary to sepsis deriving from ulcerations.19
Uremic pruritus. The detrimental effect ESRD has on microcirculation impairs wound healing not only by diminishing the flow of nutrients and oxygen to the wound, but by degenerating sweat glands and causing chronic itching.20 The repetitive trauma of uremic pruritus caused by the itching compromises the skin, not only potentially delaying wound healing but creating a risk factor for wound development.21
Uremia. As toxins accumulate in the body secondary to renal failure, they have an adverse effect on essential wound healing stages. Toxins impair platelet function, leading to diminished hemostasis, the first stage in wound healing.9 Inflammation and proliferation, the second and third stages of wound healing, respectively, are already diminished in patients with diabetes. Uremia further diminishes these stages by not only exacerbating the adverse effects diabetes has on healing but independently contributing its own mechanisms. For example, the accumulation of interleukin-6 (IL-6) in uremia drives chronic inflammation, keeping the wound in the second stage. Uremia also inhibits fibroblasts, delays proliferation (stage three) and decreases substantial granulation tissue that is imperative to healing.20,22-23
Hemodialysis. While dialysis is essential to survival for patients with ESRD, hemodialysis does not come without adverse effects of its own, especially on wound healing.
Authors have observed a significant decrease in transcutaneous oxygen (TcPO2) during and after hemodialysis.24-26 Specifically, authors compared the TcPO2 to the dorsal foot to baseline measurements during, immediately following and at one, two and four hours after hemodialysis. Hinchliffe and colleagues found that the baseline TcPO2 to the dorsum of the foot continuously and significantly dropped at each time interval, demonstrating a steadily declining trend for at least four hours after dialysis.24 Researchers have attributed this drop in TcPO2 in the lower extremity not only to the systemic hypoxemic state the body acquires during hemodialysis but also to the fluid shift that is produced to preserve central circulation by decreasing peripheral blood flow.24-26 Therefore, the drop in TcPO2 limits pedal skin perfusion and the delivery of nutrients crucial for wound healing.
Zinc. While best known as an “essential trace element,” zinc has a profound influence on wound healing. Zinc not only has inherent protective elements against bacterial toxins and reactive oxygen species that can delay wound healing, it is also a cofactor for the enzymatic pathway that improves autolytic debridement of wounds and epidermal cell migration.27-28 Low serum zinc levels are present in 40 to 78 percent of patients with chronic kidney disease. These low levels are secondary to the coincidental excretion and filtration of zinc during hemodialysis as well as decreased absorption in the gut, and a decreased intake of zinc due to dietary restrictions.29
Protein. Nutrition plays an imperative role in wound healing as it is needed to support the increase in metabolic demand secondary to inflammation and cellular activity. Researchers have directly correlated ESRD with increased protein catabolism and protein malnutrition.30 This depletion in protein specifically impairs the last three stages of wound healing. The inflammatory phase is prolonged due to the inhibition of collagen synthesis and fibroblast proliferation, the angiogenesis of the proliferative phase is impaired, and wound remodeling is inhibited.31-32 Protein deficiency not only directly affects the process of wound healing, it also impairs the immune system by inhibiting leukocyte phagocytosis, increasing the susceptibility to infection.33-34
Immune system. As noted above, immunosuppression in patients with ESRD is not only caused by a protein deficiency but by the presence of uremic toxins as well, increasing the chance of delayed wound healing via infection. Researchers have noted the correlation between uremic toxins and immunodepression with adverse effects on neutrophils, monocytes and dendritic cells.35 While infections are known to delay wound healing, it is also important to recognize that immunocompromise and septicemia increase the mortality rate of patients with ESRD by 100 to 300 times.36
Anemia. It has long been known that anemia of chronic disease is well correlated with ESRD. In fact, the extent of renal damage directly correlates to anemic severity.37 The kidney is responsible for detecting the oxygen availability to tissues and releasing erythropoietin, a red blood cell production stimulator, in response to cellular hypoxia.38-39 Therefore, the organ damage in ESRD inhibits not only the production of new red blood cells to overcome anemia but the perception that the body is even in a hypoxic, detrimental state is also hindered. These consequences negatively affect wound healing by impairing the perfusion of oxygen and nutrients to the lesion site.
Iron. Treatment options for anemia include iron supplementation to optimize erythropoiesis. However, recent studies have demonstrated that an iron overload, which increases ferritin concentrations, will actually inhibit angiogenesis by suppressing the autocrine stimulation of the vascular endothelial growth factor (VEGF) pathway.40 Inhibiting endothelial cell proliferation, migration and formation ultimately inhibits the proliferative stage of healing. Researchers have found that the use of iron chelators such as deferoxamine (Desferal, Novartis Pharmaceuticals) can be beneficial in preventing iron overload and the deleterious effects it has on wound healing.41-43
Neuropathy. Uremia is a proven independent risk factor for the development of neuropathy, which has an incidence between 60 to 100 percent in patients with ESRD.44 The same long-term sequelae and complications that diabetic neuropathy poses to wound healing are present in uremic neuropathy. These manifestations include paresthesias, diminished deep tendon reflexes, weakness and muscle atrophy. Muscle wasting, specifically to the intrinsic musculature, can lead to claw toe deformities that increase the risk of ulceration at points of maximum pressure while also impeding the ability to heal. Hypohidrosis and hypotension are two autonomic dysfunctions of neuropathy that negatively effect wound healing by, respectively, decreasing skin turgor and increasing the risk of fissures and wounds, and causing a fluid shift away from peripheral cutaneous capillary beds, decreasing microvascular sufficiency.45-46
ESRD And Patient Adherence: What You Should Know
Adherence. End-stage renal disease drastically changes a patient’s life with frequent physician visits, an increase in hospitalizations, dietary restrictions and body changes. These life changes have an immense psychological impact on patients.
There are three distinct phases for patients undergoing dialysis.47 The first is considered the “honeymoon” phase, in which the patient feels initially better secondary to the filtration of uremic toxins but this phase is followed by a phase of “disillusionment” within the first year of treatment. Patients begin to become depressed and disappointed after realizing that dialysis is not a cure, but a lifelong treatment. Some patients never progress from this phase and this is when patient adherence becomes problematic.
Wound healing is tedious and demands strict adherence from the patient. Physicians cannot force adherence upon a patient but it is important to understand this phase as physicians can help focus patient discussions. Educating and empathizing with patients, listening to concerns and working with patients to achieve their personal goals can improve their quality of life, and help advance patients to the last phase of “resolution and acceptance.”
A Guide To Effective Treatment Of Wounds In Patients With ESRD
Reviewing and understanding the effects ESRD has on wound healing is crucial to formulate optimal treatment plans. Present day treatment options include local wound care, hyperbaric oxygen therapy, revascularization and amputation. Medical management considerations can play an important role in wound healing potential. Management should include noninvasive and invasive vascular workups to assess blood flow as well as prealbumin blood levels to determine the nutritional status of patients. One must also carefully monitor iron overload in those receiving iron supplementation for comorbid anemia.
The local treatment of wounds for patients with ESRD is similar to standard ulceration protocols, such as offloading and local wound care, but one must take special considerations for patients with ESRD. One must have a high index of suspicion for wound infection in patients with ESRD as there is a multitude of underlying factors that increase the risk of infection in this population. When performing local wound care, clinicians should assess for uremic pruritus. If there are clinical signs of xerosis and symptomatic itching, available treatment options include emollients (preferably those high in water content), topical analgesics, oral antihistamines, gabapentin and antidepressants.49-53
While there is a plethora of wound care products in today’s market, one should consider products that contain zinc. As discussed, zinc has inherent properties for optimizing local wound care and zinc levels are diminished in patients with kidney disease.27 Therefore, one can utilize the topical administration and use of zinc oxide paste bandages (Unna boot) to reduce infections and enhance epithelialization.
Other wound care treatment considerations include the use of hyperbaric oxygen therapy (HBOT). While the literature is split on the effectiveness of this therapy, one can make the argument that with the decrease in TcPO2 following hemodialysis, HBOT can help improve local tissue perfusion.54-55
While local wound care is imperative, researchers have reported that the healing rate for wound care alone is only 20 percent in patients with ESRD and critical limb ischemia (CLI), again highlighting the need for medical management and vascular studies.56-57 A meta-analysis of lower extremity bypass surgery in over 1,000 patients with ESRD found that revascularization can result in limb salvage.58
However, studies have shown that clinicians need to consider preoperative nutritional status prior to revascularization in this cohort. The National Surgical Quality Improvement Program observed that obese and underweight patients, with a body mass index of >30 kg/m2 and <18.6 kg/m2 respectively, had increased mortality rates after lower extremity bypass surgery.59 Kumada and coworkers also found that an elevated C-reactive protein was a significant marker for major amputation and death in patients undergoing lower extremity bypass.60
Percutaneous vascular intervention is an option for debilitated patients who are not prime bypass candidates but the Vascular Study Group of New England has shown that there is not a significant difference in amputation-free survival or overall survival rates with this technique in comparison to bypass.61 Other independent risk factors that significantly increase the one-year mortality after revascularization include CLI, coronary artery disease, chronic obstructive pulmonary disease, age over 80 and dependent ambulatory status.62
Regardless of revascularization, studies have found that even with a patent bypass, many patients still require amputation.63 Not only did Ramdev and colleagues observe that 52 percent of their patients with ESRD needed amputation despite having patent grafts, they also noted the limb salvage rates after bypass were substantially lower in these patients than the general population. The limb salvage rates for patients with ESRD following lower extremity bypass was 80 percent at both one and three years whereas the general population limb salvage rate was 87 percent at five years.
Final Treatment Considerations
This begs the question: Should certain patients undergo primary amputation or revascularization? Edwards and colleagues concluded that primary amputation might be the treatment of choice instead of revascularization after their study found significantly lower limb salvage rates following bypass in their patients with ESRD, even though the primary patency rates were comparable in patients with or without ESRD.
To this day, there is only one treatment algorithm that can help guide the decision of primary amputation versus limb salvage: the wound, ischemia and foot infection (WIfI) system by the Society for Vascular Surgery Lower Extremity Guidelines Committee.65 This classification system predicts amputation risk for threatened lower limbs. While this system is not specifically designed for patients with ESRD, it is intended for any patient with a diabetic foot ulcer, non-healing foot ulcer, lower extremity gangrene or ischemic rest pain. One can utilize WIfI to determine the likelihood of limb salvage or if primary amputation should be the standard of care in certain circumstances.
Ms. Behan is a fourth-year podiatric medical student at the California School of Podiatric Medicine at Samuel Merritt University.
Dr. Reyzelman is an Associate Professor at the California School of Podiatric Medicine at Samuel Merritt University. He is the Co-Director of the University of California San Francisco (UCSF) Center for Limb Preservation.
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