More than skin deep? Potential nicotinamide treatment applications in chronic kidney transplant recipients

Abstract

Non-melanoma cutaneous carcinomas, or skin cancers, predominantly squamous cell carcinomas (SCCs), are the most common malignancies occurring in kidney transplant recipients (KTRs). Squamous cell carcinoma risk is dramatically elevated in KTRs, occurring at rates of up 45-250 times those reported in general populations. New non-melanoma skin cancers in KTRs with a prior non-melanoma skin cancer also develop at 3-times the rate reported in non-KTRs with the same clinical history. The unique aggressiveness of SCCs in KTRs increases patient morbidity, due to the high rate of new lesions requiring treatment, frequently surgical excision. Oral nicotinamide shows promise in the chemoprevention of the especially aggressive non-melanoma skin cancers which occur in KTRs. This benefit might be conferred via its inhibition of sirtuin enzymatic pathways. Nicotinamide's concurrent hypophosphatemic effect may also partially ameliorate the disturbed calcium-phosphorus homeostasis in these patients-a putative risk factor for mortality, and graft failure. Conceivably, a phase 3 trial of nicotinamide for the prevention of non-melanoma skin cancers in KTRs, lasting at least 12-mo, could also incorporate imaging and laboratory measures which assess nicotinamide's impact on subclinical cardiovascular and chronic kidney disease risk, and progression.

Keywords: Kidney transplantation; Niacinamide; Phosphorus; Skin neoplasms.

Figure 1

The unique aggressiveness of squamous cell carcinoma in kidney transplant recipients. Deeply invasive, recurrent, poorly differentiated and ulcerated squamous cell carcinoma in a 73-year-old female kidney transplant recipient with background alopecia from prior radiation therapy for this squamous cell carcinoma.

Figure 2

Nicotinamide-SIRT binding. At high concentrations, NAM can bind to SIRT when it contains the O-alkyl-amidate intermediate, resulting in “NAM exchange”, reforming NAD⁺ and acetyl-lysine, and decreasing deacetylation activity - a process unique to NAM, not NA. Reproduced from[18]. NA: Nicotinic acid; NAM: Nicotinamide.

Figure 3

Phosphorus-lowering effect of nicotinic acid in chronic kidney disease. Mean serum phosphorus concentrations in dyslipidemic patients with stage 3 chronic kidney disease receiving extended release niacin-laropiprant, or placebo. Error bars are standard errors. Reproduced from Ref. [24].