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| EDITORIAL COMMENTARY |
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| Year : 2018 | Volume
: 64
| Issue : 1 | Page : 5-6 |
Vitamin D in diabetic nephropathy
RA Prabhu, K Saraf
Department of Nephrology, Kasturba Medical College and Hospital, Manipal, Karnataka, India
| Date of Web Publication | 30-Jan-2018 |
Correspondence Address:
R A Prabhu
Department of Nephrology, Kasturba Medical College and Hospital, Manipal, Karnataka
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jpgm.JPGM_311_17
How to cite this article:
Prabhu R A, Saraf K. Vitamin D in diabetic nephropathy. J Postgrad Med 2018;64:5-6 |
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).[3],[4] 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;[10],[11] 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.
| :: References | |  |
| 1. | Zehnder D, Bland R, Williams MC, McNinch RW, Howie AJ, Stewart PM, et al. Extrarenal expression of 25-hydroxyvitamin D (3)-1 alpha-hydroxylase. J Clin Endocrinol Metab 2001;86:888-94.  |
| 2. | Ravani P, Malberti F, Tripepi G, Pecchini P, Cutrupi S, Pizzini P, et al. Vitamin D levels and patient outcome in chronic kidney disease. Kidney Int 2009;75:88-95. |
| 3. | Melamed ML, Thadhani RI. Vitamin D therapy in chronic kidney disease and end stage renal disease. Clin J Am Soc Nephrol (CJASN) 2012;7:358-65. |
| 4. | Mizobuchi M, Morrissey J, Finch JL, Martin DR, Liapis H, Akizawa T, et al. Combination therapy with an angiotensin-converting enzyme inhibitor and a vitamin D analog suppresses the progression of renal insufficiency in uremic rats. J Am Soc Nephrol 2007;18:1796-806. |
| 5. | Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1, 25-Dihydroxyvitamin D (3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest 2002;110:229-38. |
| 6. | de Zeeuw D, Agarwal R, Amdahl M, Audhya P, Coyne D, Garimella T, et al. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. Lancet 2010;376:1543-51. |
| 7. | Bhan I, Dobens D, Tamez H, Deferio JJ, Li YC, Warren HS, et al. Nutritional vitamin D supplementation in dialysis: A randomized trial. Clin J Am Soc Nephrol 2015;10:611-19. |
| 8. | Banerjee S, Basu S, Sen A, Sengupta J. The effect of vitamin D and calcium supplementation in paediatric steroid-sensitive nephrotic syndrome. Pediatr Nephrol [Internet] 2017;32:2063-70. Available from: https://doi.org/10.1007/s00467-017-3716-2. [Last accessed date on 2017 Oct 11]. |
| 9. | Liyanage P, Lekamwasam S, Weerarathna TP, Liyanage C. Effect of vitamin D therapy on urinary albumin excretion, renal functions, and plasma renin among patients with diabetic nephropathy: A randomized, double-blind clinical trial. J Postgrad Med 2018;64:10-5. [Full text] |
| 10. | Alborzi P, Patel NA, Peterson C, Bills JE, Bekele DM, Bunaye Z, et al. Paricalcitol reduces albuminuria and inflammation in chronic kidney disease: A randomized double-blind pilot trial. Hypertension 2008;52:249-55. |
| 11. | Fishbane S, Chittineni H, Packman M, Dutka P, Ali N, Durie N. Oral paricalcitol in the treatment of patients with CKD and proteinuria: A randomized trial. Am J Kidney Dis 2009;54:647-52. |
| 12. | Thadhani R, Appelbaum E, Pritchett Y, Chang Y, Wenger J, Tamez H, et al. Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: The PRIMO randomized controlled trial. JAMA 2012;307:674-84. |
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