TO THE EDITOR
Vitamin D deficiency (VDD) is a major global health problem that extends far beyond bone and mineral metabolism. Contemporary pooled analyses suggest that, globally, approximately 15.7% of individuals have 25-hydroxyvitamin D (25OHD) concentrations below 30 nmol/L, and 47.9% have concentrations below 50 nmol/L, indicating that VDD and insufficiency affect a substantial proportion of the world’s population[1]. Importantly, the burden is particularly pronounced in Asia, where a recent systematic review and meta-analysis reported a high prevalence of VDD despite abundant sunlight across many countries[2]. In South Asia, the problem appears even more pronounced; one systematic review found that around 68% of adults were vitamin D-deficient[3]. These data underscore that VDD should not be regarded as a niche nutritional problem but rather as a broad metabolic and public health issue relevant across multiple organ systems and disease states[4].
The relevance of VDD is even greater in nephrology. Patients with chronic kidney disease (CKD) often have reduced vitamin D stores and altered vitamin D metabolism, and these abnormalities may persist into the post-transplant period[5]. Kidney transplant recipients are particularly susceptible because they frequently enter transplantation after prolonged CKD, reduced outdoor activity, and prior dialysis exposure, and they remain exposed after transplantation to glucocorticoids, calcineurin inhibitors, persistent metabolic disturbances, and other factors that may adversely affect vitamin D status[6]. Thus, VDD is common in kidney transplantation not only because of geography or lifestyle, but because it is embedded in the biology and treatment context of advanced kidney disease and transplantation itself.
The potential link between vitamin D and glucose metabolism has been a sustained focus of scientific interest. Vitamin D receptors are present in pancreatic beta cells and other insulin-responsive tissues, and vitamin D has been implicated in insulin secretion, calcium-dependent beta-cell function, systemic inflammation, and peripheral insulin sensitivity. These mechanisms provide biological plausibility for the hypothesis that VDD may contribute to dysglycemia and diabetes risk[7]. Epidemiologic evidence broadly supports this view. In prospective population-based studies, lower initial levels of 25OHD have been linked to an increased risk of developing type 2 diabetes (T2D); one cohort study combined with a meta-analysis found a pooled odds ratio of 1.50 for incident diabetes when comparing individuals in the lowest vitamin D quartile to those in the highest[8]. A separate systematic review and meta-analysis of prospective studies likewise concluded that lower vitamin D status was associated with a higher risk of T2D and adverse metabolic outcomes[9].
However, the relationship between vitamin D and diabetes should not be oversimplified. Observational associations do not necessarily establish causality, and low vitamin D may, in some cases, reflect obesity, reduced physical activity, chronic inflammation, poor nutritional status, or broader ill health rather than acting as a direct diabetogenic driver[10]. Moreover, some studies evaluating vitamin D intake rather than measured circulating levels have not demonstrated a clear protective association. Prospective observational studies, however, associate lower vitamin D status with a higher risk of incident T2D and adverse metabolic outcomes[11]. In adults with prediabetes, an individual participant data metaanalysis of three randomized trials found that vitamin D supplementation reduced the risk of diabetes by 15% compared with placebo, suggesting a modest preventive effect in selected highrisk populations[12]. Importantly, these trials were conducted in adults with prediabetes; the individual studies were underpowered to detect small effects, and the pooled 15% relative risk reduction is modest and may not generalize to populations without prediabetes or to other clinical settings. Furthermore, Mendelian randomization analyses indicate that genetically higher lifelong 25OHD concentrations are not associated with materially lower T2D risk, despite the positive associations observed in conventional observational studies[13]. Taken together, these lines of evidence suggest that low vitamin D status may, at least in part, serve as a marker of adverse metabolic health rather than a strong, independent causal driver of diabetes risk. These data do not establish an identical benefit in kidney transplantation, but they support the hypothesis that correcting severe VDD could influence post-transplant glycemic outcomes in ways that are biologically and clinically plausible.
Post-transplant diabetes mellitus (PTDM) is one of the most important metabolic complications after kidney transplantation. PTDM is associated with adverse cardiovascular outcomes, increased overall morbidity, and worse long-term patient and graft outcomes. Its pathogenesis is multifactorial, involving age, adiposity, ethnicity, family history of diabetes, preexisting insulin resistance, and transplant-specific exposures such as corticosteroids and calcineurin inhibitors[14]. Glucocorticoids and calcineurin inhibitors not only promote insulin resistance and beta-cell dysfunction but may also affect vitamin D metabolism and behaviors that influence vitamin D status, such as weight gain, reduced outdoor activity, and changes in dietary patterns. These overlapping pathways underscore the potential for confounding, as patients receiving more intensive immunosuppression may simultaneously have lower 25OHD concentrations and a higher intrinsic risk of PTDM, making rigorous adjustment for immunosuppressive exposure essential when interpreting observational associations between vitamin D and PTDM[14]. Because PTDM risk is strongly influenced by tacrolimus use and cumulative glucocorticoid exposure, any attempt to estimate the independent contribution of VDD must carefully account for differences in immunosuppressive regimens, as prior transplant cohorts have shown that the association between low vitamin D and PTDM may be accentuated in tacrolimustreated recipients[14].
Within this framework, VDD is an especially attractive clinical target because it is common, measurable, and potentially modifiable. If VDD meaningfully contributes to metabolic instability after transplantation, identifying and correcting the deficiency may offer a practical means to improve PTDM risk stratification and possibly prevention[6]. Existing transplant literature supports this possibility. In a multicenter cohort study of kidney transplant recipients, lower pretransplant vitamin D levels independently predicted PTDM, and the authors proposed that vitamin D may represent a novel modifiable risk factor after kidney transplantation[15]. Broader reviews of vitamin D in kidney transplantation similarly emphasize that deficiency is highly prevalent and may be associated with post-transplant metabolic and graft-related outcomes[6]. Although the evidence remains predominantly observational, it is broadly consistent across several cohorts and transplant settings.
It is within this evolving context that Singh et al’s study[16] should be interpreted. In their prospective single-center study published in the World Journal of Nephrology, 72 kidney transplant recipients were followed for 1 year, and 32 (44.4%) developed PTDM[16]. Pre-transplant VDD, defined as 25OHD < 20 ng/mL, was present in 61.1% of the cohort. Twenty-six (81.2%) patients with PTDM had VDD, compared with 18 (45.0%) without PTDM (P = 0.007). On univariable analysis, VDD was associated with PTDM, and this association remained significant in multivariable regression, with an adjusted odds ratio of 8.21 (95% confidence interval: 2.19-30.75)[16]. The importance of the study extends beyond its positive findings. First, it provides data from a tropical South Asian setting, which is valuable because region-specific transplant evidence on vitamin D and PTDM remains limited. Second, it shows that clinically meaningful VDD remains highly prevalent even in an environment where sunlight exposure might be assumed to protect against deficiency[3]. Third, the prospective design, clearly defined vitamin D thresholds, specified assay method, and explicit PTDM diagnostic criteria enhance the internal validity of the findings. In this sense, Singh et al[16] contribute not only another observational association but also a regionally important signal that merits broader attention. At the same time, it is important to clearly acknowledge the study’s limitations. Given that this estimate is based on only 32 PTDM events, includes several covariates in the model, and is accompanied by a very wide confidence interval, the true effect size is likely substantially smaller[16]. Residual confounding is still possible, as VDD may coexist with factors such as obesity, frailty, nutritional problems, lower physical activity, systemic inflammation, and other unmeasured variables that could influence PTDM risk[6,10]. Moreover, the index study was conducted at a single South Asian center, where high background prevalence of VDD, differences in body composition, and population-specific polymorphisms in the vitamin D receptor may influence both vitamin D status and PTDM susceptibility. As a result, these findings may not be directly generalizable to Western transplant populations or other ethnic groups, underscoring the need for larger, multiethnic cohorts to clarify the consistency and magnitude of any association between vitamin D and PTDM across diverse clinical contexts. Additionally, observational studies cannot definitively establish whether VDD is causal, permissive, or simply an indicator of broader metabolic vulnerability[17]. Consequently, this study should be viewed as strengthening hypotheses rather than conclusively proving them.
Despite these caveats, the clinical implications are substantial. Pre-transplant measurement of 25OHD is inexpensive, widely available, and easy to integrate into the routine assessment of transplant candidates. Severe deficiency, for example, 25OHD concentrations below approximately 10-12 ng/mL, may help identify individuals who need more intensive glucose surveillance during the first year after transplantation, when PTDM most commonly emerges[14]. In practice, it would be reasonable for transplant programs to measure 25OHD in all candidates, treat those with deficiency, and aim to raise levels into the sufficient range (e.g., ≥ 30 ng/mL) before transplantation or as early as feasible thereafter, as this is likely to be most relevant during the pretransplant evaluation and first posttransplant year. More broadly, the findings support incorporating vitamin D status into composite pre-transplant metabolic risk models alongside age, body mass index, family history, and immunosuppressive exposure[14]. While vitamin D supplementation has not yet been shown to prevent PTDM, addressing severe deficiency remains important for bone and mineral health, and potential metabolic benefits should not be overlooked[17]. Native vitamin D preparations, such as cholecalciferol or ergocalciferol, are typically used to treat nutritional deficiency and raise circulating 25OHD, whereas active vitamin D analogs, such as calcitriol, are prescribed primarily for the management of CKD-mineral and bone disorder rather than for PTDM prevention[18,19]. For PTDM risk stratification, the priority is to identify and correct nutritional VDD with native vitamin D to achieve sufficient 25OHD levels, consistent with existing bone health and CKD-mineral and bone disorder recommendations, while recognizing that current transplant and PTDM guidelines do not specifically recommend vitamin D supplementation solely to prevent PTDM[19,20].
Future research should move beyond repetitive observational confirmation and toward causal testing. Larger multicenter prospective cohorts are needed to determine whether the association between VDD and PTDM is consistent across ethnic groups, climatic regions, baseline metabolic states, and immunosuppressive strategies. More importantly, randomized controlled trials should assess whether correcting severe VDD before or soon after transplantation can reduce PTDM incidence or improve glycemic trajectories. Such trials should preferentially enroll kidney transplant candidates or recent recipients with severe deficiency (e.g., 25OHD < 10-12 ng/mL) and additional metabolic risk factors, such as prediabetes, obesity, or a family history of diabetes; use dosing regimens that reliably achieve 25OHD levels ≥ 30 ng/mL; rigorously account for tacrolimus exposure and cumulative glucocorticoid dose; and specify a primary endpoint based on consensus PTDM diagnostic criteria within the first post-transplant year. Such studies should be multicenter and adequately powered to detect clinically meaningful differences in PTDM incidence and related metabolic outcomes, moving the field beyond associative data toward definitive causal inference. A precisionrisk approach of this kind is likely to be more informative than asking whether vitamin D supplementation benefits all transplant recipients equally.
Overall, the evidence supports a cautious but clinically relevant conclusion. VDD is widespread globally, especially in South Asia, and is biologically linked to glucose dysregulation. It is increasingly associated with both T2D and PTDM in observational studies. The research by Singh et al[16] provides valuable data from a region with limited previous evidence and bolsters the case that vitamin D status warrants more attention in kidney transplant care. While the field has not yet established definitive causality or proven that supplementation guarantees prevention, it recognizes VDD as a clinically significant and potentially modifiable factor in PTDM risk. In this context, VDD may represent an underutilized opportunity for risk assessment, targeted monitoring, and future preventive strategies in kidney transplant recipients.
