Vitamin D in diabetic nephropathy.

Vitamin D has calciotropic and pleiotropic effects mediated through vitamin D receptor (VDR) expressed in kidneys, including podocytes, intestine, bones, parathyroid glands, pancreatic beta cells, monocytes, and T-cells.[1] Vitamin D deficiency occurs in 60% of chronic kidney disease (CKD) stages 4 and 5, and is associated with progression and all-cause mortality.[2]

Proteinuria is a surrogate marker of progressive CKD with inflammation playing a part in it. Podocytes express 1-α-hydroxylase and VDR. Calcitriol has shown antiproteinuric effects in multiple animal models alone and in combination with angiotensin receptor blockers (ARBs).[34] In animal studies calcitriol reduces mesangial proliferation, suppresses renin, and negatively regulates renin angiotensin aldosterone system (RAAS),[5] left ventricular hypertrophy, and left ventricular diastolic measures. Through its suppression of transforming growth factor-β, macrophage infiltration, and transcription factor nuclear factor-κβ activity, it has additional antiinflammatory and antifibrotic activity, which may contribute in reno-protection over and above RAAS inhibition. However, these effects are not corroborated fully in humans.

In the VITAL study,[6] paricalcitol did not reduce plasma renin in spite of reduction in albuminuria. In the current study, a significant reduction in plasma renin was noted, which correlated with decrease in albuminuria (although the doses of ARBs across the groups were not stable and not matched). Randomized controlled trial (RCT) design is an important strength of this study as there is limited such evidence evaluating the use of vitamin D in diabetic nephropathy in RCTs. However, use of low grade albuminuria as sole diagnostic criteria of CKD and its use as surrogate endpoint is debatable because guidelines recommend “persistent albuminuria” (repeated over 3–6 months, two readings) to meet definition criteria. Also, short duration of follow-up of 6 months makes evaluation of effects on glomerular filtration rate (GFR) difficult as salient results noted may be due to better blood pressure control. Any treatment evaluating the effect on GFR typically looks for follow-up of minimum 18 months. These methodological pitfalls limit generalizability of results, and therefore, further studies are needed.

Therapeutic use of VDR agonists to reduce proteinuria requires a balance between beneficial and adverse effects. In the DIVINE study,[7] nutritional vitamin replacement to achieve sufficiency (>32 ng/ml) was found to be safe in incident hemodialysis population. However, a recent RCT of vitamin D in nephrotic syndrome reported significantly higher incidence of hypercalciuria in treated patients.[8] In addition, proposed pleiotropic benefits were not observed. Intriguingly, in the current study,[9] supranormal levels of vitamin D were achieved without adverse effects. Thus, appropriate dosage of vitamin D remains uncertain.

Other RCTs evaluating paricalcitol have found to lower high-sensitivity C-reactive protein;[1011] but no alteration of left ventricular mass index or improvement in diastolic dysfunction (PRIMO Study[12]). Compared to ARBs, paricalcitol is effective even with high salt intake, which is being studied in the PROCEED trial (NCT01393808).

In conclusion, the beneficial effects which are realized with animal studies have to be confirmed in humans. The long-term clinical outcomes of effects on surrogate markers such as proteinuria, cardiac indices remain unanswered. Currently, there is no evidence to support clinical use of vitamin D for its proposed pleiotropic benefits (proteinuria and others). Trials looking at reno-protective benefits should involve validated endpoints and adequate follow-up duration. For a disease such as CKD with multifactorial etiology and risks, novel therapies such as these holds promise both for research and patient benefits. The present study contributes in a small way toward that.

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Nil.

Conflicts of interest

There are no conflicts of interest.