Beyond revascularization – Quality of hemodialysis and its impact on amputation prevention

End-stage renal disease (ESRD) and diabetes mellitus have been persistently associated with critical limb ischemia (CLI) and amputations. ¹ The increased risk associated with ESRD is likely driven by the presence of concomitant long-term diabetes mellitus, and is likely cumulative with both. While diabetes has been associated with neuropathy and peripheral artery disease (PAD), ESRD without the presence of diabetes has also shown these associations.^2–4 Furthermore, the presence of both diabetes and ESRD has been associated with increased foot complications compared to those with diabetes mellitus without renal replacement therapy. ⁵

Given the increased risk of amputation in the CLI population, the main goal of therapy has classically been revascularization, wound care, and infection control to prevent amputation.^6–8 However, more recently, important other endpoints such as time to ambulation, time to wound healing, and complete wound healing have been promoted. ⁹ While revascularization, in conjunction with excellent wound care, is the primary approach to promote wound healing and prevent amputations, other potential strategies are being considered. To address one of these approaches, Hioki and colleagues conducted a retrospective analysis to examine the association between calcium-phosphate (CaP) homeostasis and amputation-free survival (AFS) in patients with CLI and ESRD after endovascular treatment (EVT). ¹⁰

Using data from two centers within Japan, they identified 221 consecutive patients with CLI on hemodialysis (HD) who underwent successful endovascular therapy. The primary outcomes were AFS and all-cause mortality. The authors used a cutoff value of 55 mg²/dL² for CaP product to assess the relationship between CaP homeostasis with AFS and all-cause mortality. The majority (> 93%) had tissue loss (Rutherford classification V and VI) and significant below-knee arterial disease. Interestingly, there was no association between serum phosphorus, calcium, and AFS or all-cause mortality; however, patients with a serum CaP product ⩾ 55 mg²/dL² had significantly lower AFS. There was also a dose-dependent association noted between the quartile of CaP product and the primary outcomes, although this did not reach statistical significance. Furthermore, the association between CaP product and outcomes persisted despite multivariable adjustments.

We congratulate Hioki and colleagues for presenting this important and potentially modifiable risk factor for amputation in patients with ESRD. Their results, if reproduced, may have important prognostic and clinical consequences. However, the following important issues should be considered. In the current study, the higher CaP product values were mainly driven by higher phosphate levels, as serum calcium levels were comparable in the two groups. High phosphate levels can be a consequence of under-treatment with phosphate binders, poor compliance with dietary restriction or use of calcium-based binders (net positive calcium balance), or inadequate dialysis treatments. In patients with an elevated CaP product, despite dietary and medical optimization, frequent and longer dialysis treatments can be used to correct mineral metabolism derangements. ¹¹ Another limitation of this study is the relatively small sample size and small number of events, with only 21 major amputations. The quality of dialysis and the success of endovascular therapy is unknown. Other important factors such as wound size and infection rates are not reported. Importantly, medical therapy among study patients was not optimal, with few patients on statin therapy.

Whether CaP homeostasis has a direct impact on wound healing is unknown, nor are there studies that have examined its effect on future calcifications. Mineral and bone metabolism is also often implicated in dialysis patients who present with calcific uremic arteriolopathy (calciphylaxis), where medial calcification of arterioles leads to ischemia. ¹² Despite these important issues, the present study raises important questions about the role of HD in patients with lower extremity wounds and ESRD. For example, alternative filtration techniques or more frequent dialysis to lower CaP product in patients with tissue loss or gangrene may be necessary to allow faster healing.

Alternatively, an elevated CaP product may just represent a marker that identifies high-risk patients. Recent data indicate that in patients with ESRD, amputations were mainly driven by the inability to achieve optimal wound care rather than graft failure or thrombosis. ¹³ Whether improved or more frequent dialysis would have a direct impact on wound healing among patients with CLI is yet to be determined. Future studies should examine the association between CaP product and time to wound healing or complete wound healing, so that the impact of CaP homeostasis on wound healing is better understood.