Several authors have noted a relationship between ESRD and LEA. Within one of the largest studied cohorts of diabetic subjects who have eGFR measurements, we have shown a strong association, not just with ESRD, but between the severity of CKD and the onset of both DFU and LEA among those with diabetes. Whereas this association is greatest for those with the most severe CKD, even those with less severe CKD were approximately two times more likely to develop a foot ulcer or undergo an LEA than those with minimal to no impairment (). This association was present among those without clinically apparent PAD. To confirm the appropriateness of our database and analysis, we were also able to show, as expected, an association between DFU or LEA and hyperglycemia, PAD, peripheral neuropathy, hypertension, history of myocardial infarction, age, previous history of DFU, previous history of LEA, and ESRD.
Traditionally, the complications of diabetes have been divided into those due to microvascular disease and those due to macrovascular disease. Microvascular complications include retinopathy, nephropathy, and peripheral neuropathy. Macrovascular diseases include coronary heart disease, stroke, and PAD/claudication. Exactly where DFUs and LEA fit into this scheme is not always clear. Many of these diabetic individuals have neuropathy and/or PAD. This might imply that these are both macro- and microvascular illnesses.
In our study we were able to explore DFU and LEA in individuals with or without clinically apparent PAD. We were able to show a relationship between these outcomes and progressive CKD. Although there may be many potential mechanisms used to explain the onset of CKD, DFU, and LEA in those with diabetes, it is fascinating to note that structurally in many ways the onset of CKD many be similar to the onset of DFU and/or LEA. As a consequence of hyperglycemia different cell types, such as mesangial cells, which have some phenotypic properties similar to those of fibroblasts, and podocytes, are damaged (
17). These cells are damaged from hyperglycemia, but the damage is also physically attributable to the trauma induced by hypertension (
18). Unlike renal cells, the cells of the dermis may be replenished from neighboring cells, transient amplifying cells local to the wound, and bone marrow–derived cells. One might hypothesize that the onset and progression of CKD might serve as an early marker (not actually a risk factor) because severe damage occurs first in the kidney (cells most sensitive to hyperglycemia that cannot replenish) and then later in the skin, which can replenish, resulting in the onset of DFU and ultimately LEA.
In the setting of a DFU, local trauma (e.g., walking, poor-fitting shoes, plantar contact with hard objects, and others) is often thought to initiate foot ulcers (
19). Interestingly, in a recent secondary analysis of a randomized clinical trial of footwear, which looked only at one form of trauma that was due to daily weight bearing, the authors noted that by itself this form of trauma was not directly associated with DFUs (
19,
20). There may be many explanations for this result. Our preceding hypothesis might help to explain this finding and to explain why trauma does not cause wounds in everyone with diabetes; i.e., before trauma results in a clinically significant wound, an individual's ability to repair must first be altered. This explanation does not diminish the importance of trauma as the likely cause of the initial insult that results in a DFU or LEA, but it may be that CKD, neuropathy, PAD, and many other complications of diabetes are on the same causal pathway related to the progressive inability to repair. Statistically, if this is true, then in our study we underestimated the magnitude of the associations that we report by adjusting our models for PAD, neuropathy, and so on. As an alternative explanation, circulating factors that directly affect wound repair and ultimately are responsible for LEA and DFU, may exist as a consequence of progressive CKD.
There are a number of important potential limitations to our study. With respect to selection bias we did not have eGFR measurements for all subjects in THIN, so perhaps the general practitioners preferentially measured creatinine in those with more severe renal disease who were most likely to develop a DFU or undergo an LEA. This is unlikely because this association is not well known. In addition, the completion of the required examinations is a performance criterion of the general practitioners, which is linked to their pay (
www.nhsemployers.org/pay-conditions/index.cfm) (
21). A recently published audit revealed that 96% complied (
21). Our study began in 2002, before mandatory compliance and eGFR measurements were available for ~72% of subjects. After 2003 about 92% of subjects had eGFR measurements. It is also possible that general practitioners failed to diagnose or record our outcomes. If this were true then our results would have been biased to the null unless the general practitioners a priori decided that an association between eGFR, a value requiring calculation, and our outcomes existed. There could also be concerns that data are not always collected in the record for THIN. It is important to realize that per agreement with the company that organizes THIN, the record for THIN is the general practitioner's only medical record. We could have mis-specified the degree of CKD because we did not know the subjects’ ethnicity/race. Ethnicity/race is an unmeasured confounder in our study. We were able to conduct several sensitivity analyses and found that our inability to determine race/ethnicity was not likely to have influenced our measurement of eGFR. Further, Abbott et al. (
22) did note various rates of foot complications and PAD and DFU in ethnic groups. However, these authors concluded that variable rates of PAD and neuropathy at least partially explained the different rates of LEA and DFU in these ethnic groups. We did adjust for PAD and neuropathy in our study too. It is possible that important assessments such as PAD and neuropathy were measured with error. However, as in other studies they were measured by general practitioners in their practices, thereby making these assessments generalizable to other general practice settings and even to other studies such as that of Abbott et al. Because we know of no reason that the accuracy of their measurement would have been influenced by the general practitioner's knowledge of eGFR (a calculated blood test), this error is probably “nondifferential,” meaning that any bias due to this error should have resulted in an underestimate in the association between CKD and LEA or DFU.
In summary, we have demonstrated a strong association between CKD and DFU or LEA among a population-based sample of individuals with diabetes who are cared for by general practitioners in the U.K. It is important to note that demonstrating an association is not the same as showing causation, which often requires an experimental design such as a randomized clinical trial and the demonstration of a common mechanism that causes CKD and failure of the skin to heal. On the basis of our study, it is likely that CKD and DFU or LEA among those with diabetes are associated more tightly then was recognized previously. Clinically, our findings are important in that we have shown an association between even individuals with moderate CKD (eGFR <60 ml/min per 1.73m2) and an increased risk for the onset of DFU and ultimately amputation.
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