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Role of Vitamin D and Its Analogues in Diabetic Nephropathy: A Meta-analysis
CLINICAL INVESTIGATION
Role of Vitamin D and Its Analogues in Diabetic Nephropathy: A Meta-analysis D1X XSonali Gupta, D2X XMD1,2, D3X XPradeep Goyal, D4X XMD2,3, D5X XRichard S. Feinn, D6X XPhD4 and D7X XJoseph Mattana, D8X XMD1,2 1
Department of Medicine, St. Vincent’s Medical Center, Bridgeport, Connecticut; The Frank H. Netter MD School of Medicine at Quinnipiac University, North Haven, Connecticut; 3 Department of Radiology, St. Vincent’s Medical Center, Bridgeport, Connecticut; 4 Department of Medical Sciences, The Frank H. Netter MD School of Medicine at Quinnipiac University, North Haven, Connecticut
2
ABSTRACT Background: Diabetic nephropathy remains one of the most common causes of chronic kidney disease in the United States and is associated with significant morbidity and mortality. Recently, there have been emerging data highlighting the role of vitamin D and its analogue in chronic kidney disease especially diabetic nephropathy independent of its effect on bone metabolism. Methods: This study aimed to evaluate effect of supplementing vitamin D and its analogues on halting or slowing progression of diabetic nephropathy. Electronic databases (PubMed, Scopus, Google scholar) were searched and randomized controlled trials (RCTs) that investigated the use of vitamin D and its analogs for diabetic nephropathy were studied. This meta-analysis of RCTs performed in accordance with Preferred Reporting Items for Systematic review and Meta-analysis statement. Results: This meta-analysis included 9 RCTs and suggested a favorable trend with respect to an effect of vitamin D and its analogues on albuminuria though this did not reach statistical significance (MD, ¡0.17; 95% CI, ¡0.34-0.01; P = 0.06]. Serum calcium was unaffected suggesting safe use of these agents. Conclusions: Use of vitamin D and its analogues may have potential as an adjuvant therapy for reducing albuminuria and slowing progression of diabetic nephropathy but further studies are needed. Key Indexing Terms: Diabetic nephropathy; Chronic kidney disease; Vitamin D. [Am J Med Sci 2019;357(3):223−229.]
INTRODUCTION
T
he prevalence of diabetes mellitus (DM) has been increasing rapidly over the last 3 decades. Globally, the number of people affected by DM has steadily increased from 108 million in 1980 to 422 million in 2014.1 Diabetic nephropathy is the most common cause of chronic kidney disease in the United States and is found to affect at least 40% of patients with DM.2 It is associated with high cardiovascular mortality2 and there are an estimated 1.6 million deaths every year directly attributed to DM.1 In addition to strategies to prevent DM and diabetic nephropathy it is important that strategies to slow the progression of diabetic nephropathy are begun at the earliest possible time. Drugs targeting the renin angiotensin system (RAS) have become the mainstay of efforts to slow the progression of diabetic nephropathy given the critical role of the RAS in its pathogenesis and progression.3-6 A limitation of RAS targeted therapies such as angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) is a compensatory rise in renin production which
may attenuate the efficacy of RAS inhibition. Hence in addition to drugs targeting the RAS there is a need for additional therapies to help slow the progression of diabetic nephropathy. Vitamin D deficiency has been reported to be associated with the development of type 1 and type 2 DM and diabetic nephropathy.7 Recent clinical and experimental data have highlighted a potential renoprotective effect of vitamin D and its analogs independent of their action on calcium and phosphorus metabolism.8-10 The mechanism by which vitamin D and its analogs may accomplish this is not clearly understood. The aim of this meta-analysis is to evaluate the potential role of vitamin D and its analogues as a therapy for diabetic nephropathy and to summarize the available evidence.
METHODS Search Strategy Electronic databases (PubMed, Scopus, Google scholar) were searched and interventional studies that investigated the use of vitamin D and its analogs for diabetic nephropathy
Copyright © 2019 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved. www.amjmedsci.com www.ssciweb.org
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were studied. All the published articles till January 2018 were included. The search terms used were "vitamin D," "cholecalciferol," "calcitriol," "alfacalcidol," "paricalcitol," "diabetic nephropathy," "diabetic kidney disease,” "albuminuria," "proteinuria," "chronic kidney disease" and "diabetes." Boolean operators were used to combine all searches. Additional studies were added after checking the reference lists of all related publications. Inclusion and Exclusion Criteria Interventional studies that met the following criteria were included in this meta-analysis: (i) patients 18 years or older with diagnosed diabetic nephropathy; (ii) the interventions in the studies including supplementation with vitamin D3 or its analogs; (iii) albuminuria including microor macroalbuminuria; (iv) randomized controlled trial design and (v) published in the English language. Major exclusion criteria were as follow: (i) case reports, case series, letter to editors and review articles; (ii) studies whose full text could not be assessed or those with incomplete data; (iii) studies without a placebo group, observational or cross sectional studies and (iv) animal studies. Two reviewers reviewed all the literature searches and determination of eligible studies was finalized. Disagreement between the 2 reviewers was resolved through consensus or referring to a third reviewer. This meta-analysis was performed according to Preferred Reporting Items for Systematic review and Meta-analysis statement. Outcomes and Data Extraction The outcomes studied included urine albumin creatinine ratio (UACR), urine protein creatinine ratio, 24-hour urine protein excretion, urinary albumin excretion rate (UAER) and change in serum 25 (OH) vitamin D, serum 1,25 (OH) vitamin D, creatinine, calcium and parathyroid hormone (PTH). The extracted information included study design, number of participants, baseline characteristics (including age, sex, type of DM), type of interventions (including type and dose of vitamin D and therapy duration and frequency) and outcome measures. Two authors (SG and PG) independently performed data extraction and disagreements were resolved by consensus or by referring to a third author (JM). Statistical Analysis This meta-analysis was conducted to perform direct comparisons between the intervention and placebo. Review Manager Software (RevMan V5.3, 2014, Cochrane Collaboration, United Kingdom) was used for data analysis and preparing the article. The effect measures in meta-analysis were reported as the percent change (%) in the mean difference, 95 % confidence interval (CI) and their standard deviations. The mean difference and standard deviations were used for the visual representation of results in the forest plots. Interstudy heterogeneity was evaluated by the I2 test and when 224
I2 > 50%, random effect model was used, otherwise, fixed effects model was adopted. Funnel plot was used to assess potential publication bias. P < 0.05 was considered statistically significant. Quality Assessment and Risk of Bias Quality assessments of the included studies were done using Review Manager V 5.3, 2014 (Cochrane Collaboration, United Kingdom). Included studies were assessed on the basis of randomization, allocation concealment, blinding process, selective reporting and outcome measurement. Two reviewers (SG and PG) independently performed this analysis and disagreement between the 2 reviewers was resolved through consensus or referring to a third reviewer (JM).
RESULTS Search Results The search strategy resulted in a total of 381 studies from PubMed, Scopus and Google Scholar. Thirty-four studies remained for further screening after removal of duplicates and review of titles and abstracts by 2 reviewers. Among these studies, 25 studies were further excluded due to different languages of the article, nonrandomized design, being an animal study and measurement of different outcome. Nine RCTs were ultimately included in the analysis (Figure 1).11-19 Characteristics of Included Studies Of the 9 included studies, 1 was multinational,11 1 was performed in Europe,15 1 in China,17 1 in Thailand,12 1 in Malaysia,14 1 in Sri Lanka,19 2 in Iran13,18 and 1 in Turkey.16 One study included only patients with type 1 diabetes,15 1 study did not mention the type of diabetics included19 and the rest included patients with type 2 DM.11-14,16-18 At baseline, the studies included 734 patients (369 patients who received vitamin D and 365 who received placebo). Four studies used calcitriol in interventional group,12,14,16,17 2 studies used paricalcitol,11,15 1 study used cholecalciferol,13 1 study mentions use of vitamin D319 and 1 study did not specify the type of vitamin D used.18 The primary outcomes measured were as follows: percent change in UACR (5 studies),11,13,16,17,19 change in UAER (2 studies),11,15 change in 24-hour urine protein excretion (1 study)18 and urine protein creatinine index (UPCI, 2 studies).12,14 Other parameters measured were change in levels of calcium, serum creatinine, PTH, 25 (OH) vitamin D and 1.25 (OH) vitamin D. Mean duration of treatment varied from 6 weeks to 6 months. Table 1 summarizes the baseline characteristics of the patients in the included studies. Main Results The studies were grouped on the basis of the outcome measured to avoid errors and misinterpretation. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES VOLUME 357 NUMBER 3 MARCH 2019
Role of Vitamin D in Diabetic Nephropathy
Articles identiied from all sources (n= 381)
Articles after removing duplicates (n= 186) Articles excluded by screening of title and abstract (n= 152) Potentially relevant articles identiied and screened for retrieval (n=34) Excluded (n=25); Language not English (n= 12), Not RCT (n=4), animal study (n=1), Outcome measured different (n=8)
RCT included in meta-analysis (n=9) FIGURE 1. Literature search flow charts. Abbreviation: RCT, randomized controlled trial.
UAER was evaluated in 2 studies.11,15 No statistically significant change in UAER was found with vitamin D therapy (mean difference, ¡0.18; 95% CI, ¡0.43 to 0.06; P = 0.14; Figure 2). Five studies evaluated change in UACR following vitamin D therapy.11,13,16,17,19 One study could not be used in the forest plot because of missing data.16 The overall result for the remaining studies favored use of a vitamin D analogue to reduce albuminuria though this did not quite reach statistical significance [mean difference, ¡0.17; 95% CI, ¡0.34 to 0.01; P = 0.06]. There was no heterogeneity between trials (I2= 0%, P =0.95, Figure 3). Two studies evaluated UPCI,14,18 however one of these could not be used because of incomplete crude data for analysis.12 The study of Mustafar et al14 showed no significant change in proteinuria as determined by UPCI regardless of diabetes status (mean difference, ¡0.19; 95% CI, ¡0.90 to 0.51; P = 0.59) as shown in Figure 4. The other secondary outcome measured was change in serum creatinine. Pooled data from the included studies showed no statistically significant change in serum creatinine in both groups (mean difference, ¡0.15; 95% CI, ¡0.62 to 0.2, P = 0.53) though the groups showed moderate heterogeneity (I2 57%, P = 0.10, Supplementary Figure 1). Change in serum PTH, calcium and 1,25 (OH) vitamin D levels also did not reach significance (PTH: mean difference, 0.06, 95% CI, ¡0.21, 0.33, P = 0.66; calcium: mean difference, 0.08, 95% CI, ¡0.04, 0.19, P = 0.19; 1,25(OH) vitamin D: mean difference, 0.53, 95% CI ¡0.46, 1.53, P = 0.29) as shown in Supplementary Figures 2-4. However, 25 (OH) vitamin D levels differed significantly in the 2 groups and reached statistical significance (P < 0.05) as shown in Supplementary Figure 5. Subgroup analysis on the basis of the different
vitamin D receptor agonist used could not be performed because of the small number of studies. Quality Assessment of Included Studies There was great variation in the overall quality of the studies included in the analysis. The studies varied in their design, methodology, duration of intervention and primary outcome measure. Overall risk of selection bias was low as baseline characteristics of the groups were similar at the beginning of the studies although attrition bias was high as 5 studies did not mention follow-up results.11,13,15,17,18 Methods for randomization and blinding are not reported in 4 RCTs12,14,17,18 thereby resulting in high performance bias. Figure 5 shows risk bias and Table 2 shows quality assessments of the included studies. Funnel plot was used to assess potential publication bias of the included studies. No statistical significance in the 7 outcomes was found (all P values > 0.05, Supplementary Figure 6).
DISCUSSION Diabetic nephropathy is the result of complex interaction between genetic, environmental, metabolic, hemodynamic and vasoactive factors.20-22 Hyperglycemia triggers a cascade of metabolic events including activation of proinflammatory cytokines, oxidative stress induction, polyol and hexosamine influx and production of advanced glycated endproducts (AGEs). AGEs are resistant to enzymatic hydrolysis by matrix metalloproteinase and thereby accumulate leading to glomerular basement membrane thickening and mesangial expansion. AGEs also interact with receptors for AGEs leading to generation of oxygen radicals and other sequelae.
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UACR (mg/mmol) UPCR (g/g) UPCI (g/mmol) UACR (mg/g) UACR (units not mentioned) 24 hours proteinuria (mg/day) Abbreviation: MN, Multinational; UA,Urinary albumin; UACR, Urinary albumin/Creatinine ratio; UAER, Urinary albumin excretion rate; UPCR,Urinary protein/Creatinine rate.
12 weeks 16 weeks 12 weeks 6 months 12 weeks 8 weeks 6 weeks UAER (mg/24 hour) Paricalcitol 1-2 mg once daily 56.1 52.8 Calcitriol 0.25 mg once daily 59.7 61.8 Calcitriol 0.25-0.5 mg twice weekly 55 52 Calcitriol 0.5 mg daily 56 59 Vitamin D3 50,000IU monthly 58.3 57.1 Cholecalciferol 50,000IU/weeks 62.9 62.4 Vitamin D 50,000IU weekly 56 40 37.8 52 42.9 30.4 40 66.6 46.6 56.5 64 48.8 42.9 60 24 30 46 25 42 30 30 Type 1 Type 2 Type 2 Type 2 NA Type 2 Type 2
24 30 45 25 43 30 30
24 weeks 2 mg once daily 95 Type 2
93
73
65
65
64
Paricalcitol
24 weeks 1 mg once daily Paricalcitol 64 64 65 71 93 93 Type 2
De Zeeuw 2010 MN (low dose) De Zeeuw 2010 MN (high dose) Joergensen 2015 Europe Jiang 2017 China Krairittichai 2012 Thailand Mustafar 2014 Malaysia Liyanage 2018 Sri Lanka Ahmadi 2013 Iran Momeni 2017 Iran
C I C
Male sex (%)
I C
Sample size
Type of diabetes Country Study
TABLE 1. Baseline characteristics of included studies.
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I
Mean age (years)
Supplement form
Dosage
Duration of treatment
End point
24 hours UA (mg) UACR (mg/mmol) 24 hours UA (mg), UACR (mg/mmol)
Gupta et al
Hyperglycemia also influences the local renal RAS resulting in increased production of angiotensin II, which in turn causes elevation of intraglomerular pressure by preferential constriction of the efferent arteriole. Hemodynamic changes including hyperfiltration and increased glomerular perfusion are evident earlier in the course of diabetic nephropathy, well before clinical signs of renal damage are evident. Structural changes aside from glomerular basement membrane thickening and mesangial expansion include podocyte foot process effacement and disruption of the dynamic filtration barrier as a result of decreased expression and increased excretion of podocyte and slit diaphragm proteins. In addition, various growth factors are activated resulting in renal inflammation, cell growth, fibrosis, mitogenesis, differentiation, migration and apoptosis. Ultimately, these molecular changes result in glomerulosclerosis, proteinuria, tubulointerstitial fibrosis, hyalinosis and arteriosclerosis of renal vessels. The classical natural history of diabetic nephropathy consists of an early stage of microalbuminuria followed by an increase in proteinuria and progressive decline in the glomerular filtration rate. However, recent studies have shown that disease progression can differ from this model as there can be a significant deterioration in the glomerular filtration rate early in the course of diabetic nephropathy irrespective of proteinuria.23 In our meta-analysis, we have included studies which have defined diabetic nephropathy by the presence of microalbuminuria and hence our findings may not be applicable for forms of diabetic kidney disease which are nonproteinuric. Treatment with RAS inhibitors has had a major impact on diabetic nephropathy though there is a need for additional therapies. While vitamin D supplementation has become part of clinical practice guidelines for the management of abnormal bone metabolism in chronic kidney disease24 its potential role as a therapy to modulate the course of diabetic nephropathy has been less well studied until more recently.11-19 The antiproteinuric effect of vitamin D and its analogs is thought to be secondary to inhibition of renin25 though RCTs evaluating the effect of vitamin D supplementation on renin are limited. Of note, despite their antiproteinuric effect, ACEIs and ARBs lead to an increase in renin secretion26 which may offset some of their beneficial actions in diabetic nephropathy. Liyanage et al have reported a gradient of microalbuminuria suppression across levels of serum renin concentrations.19 Given that therapy with ACEIs and ARBs increases renin this suggests that vitamin D supplementation might serve as a helpful adjunct to RAS-based antiproteinuric therapy. Also of note efficacy of ACEIs and ARBs may be limited by failure to follow a low sodium diet. Paricalcitol has been shown to reduce albuminuria irrespective of dietary sodium intake19 further suggesting that vitamin D therapy might be of benefit as an addition to RAS-based treatment regimens for diabetic nephropathy. It is also worth emphasizing that in studies evaluating the effect of vitamin D (or any other THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES VOLUME 357 NUMBER 3 MARCH 2019
Role of Vitamin D in Diabetic Nephropathy
FIGURE 2. Forest plot of urinary albumin excretion rate (UAER) change in patients with diabetic nephropathy (DN).
FIGURE 3. Forest plot of urinary albumin creatinine ratio (UACR) change in patients with diabetic nephropathy (DN).
FIGURE 4. Forest plot of urinary protein creatinine ratio (UPCR) change in patients with diabetic nephropathy (DN).
FIGURE 5. Risk bias assessment of included studies.
agent) when added to an ACEI or ARB, the ACE/ARB dosing should be stable throughout the study period to help separate out an effect of the intervention (in this case vitamin D or an analog) from the ACEI or ARB. While many of the included studies in our meta-analysis clearly mention the number of patients on stable doses of ACEI/ ARBs,11,12,14,15,16 data were missing from several others.13,17,18,19 Appropriate dosage and duration of therapy with vitamin D and its analogs for a maximum antiproteinuric effect is uncertain. There is a pleiotropic effect of vitamin D receptor agonists on metabolism, inflammation and the immune system, which has gained attention and requires consideration of a potentially fine balance between beneficial and adverse effects. Bischiff-Ferrari
et al reported health benefits of vitamin D when 25(OH) vitamin D levels reached 75 nmol/L.27 The DIVINE study concluded ergocalciferol supplementation to be safe and without significant effect on blood calcium, phosphate or PTH hormone levels in incident hemodialysis patients.28 Liyanage et al reported supernormal levels of 25(OH) vitamin D (81.75 nmol/L in the intervention group) without adverse effects.19 However, Banerjee et al reported hypercalciuria in 52% of patients in intervention group emphasizing caution and a need for regular follow-up.29 Our meta-analysis showed a significant increase in 25 (OH) vitamin D levels without a significant increase in serum calcium in the intervention group suggesting vitamin D and its analogue may be safe to use in diabetic nephropathy. However, variation in study design,
Copyright © 2019 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved. www.amjmedsci.com www.ssciweb.org
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TABLE 2. Quality assessment of included studies. Studies Sample sizea Randomization Randomization methodb Allocation concealment Participant blinded Outcome measure (valid/reliable) Assessor blinded Equal follow-upc Attrition rate equal for both groups Completenessd Groups similar at baselines
De Zeeuw
Joergensen
Jiang
Krairttichai
Mustafar
Liyanage
Ahmadi
Monemi
Tiyakari
+ + + + + + + ¡ ¡ + +
+ + + + + + + ¡ ¡ + +
+ + ¡ ¡ ¡ + ¡ ¡ ¡ + +
+ + ¡ ¡ ¡ + ¡ + + + +
+ + ¡ ¡ ¡ + ¡ + + + +
+ + + + + + + + + + +
+ + + ¡ + + + ¡ ¡ + +
+ + ¡ ¡ ¡ + ¡ ¡ ¡ + +
+ + + ¡ ¡ + ¡ + + + +
Notes: (+) indicates that the measure was adequately addressed in the study. (¡) indicates that the factor was not measured, or not adequately addressed in the study. a Studies receives (+) if sample size was justified. b Studies received (+) if randomization method was specified in the study and (¡) if no method was specified. c Studies received (+) if groups were followed within 10% of each other or for the same time. d Studies received (+) if full description of those lost to follow-up was mentioned and final analysis included >80% of population.
intervention and small sample size limit generalization of the results. While our meta-analysis suggested a trend toward a favorable effect of vitamin D and its analogues on albuminuria in diabetic nephropathy our findings did not quite reach statistical significance (P = 0.06). The main strength of this study is that it is a meta-analysis of all the RCTs evaluating the effect of vitamin D receptor agonists on diabetic nephropathy. However, there were several limitations in this study. First, there is heterogeneity of data particularly in a handful of studies as regards the basis of primary outcome and vitamin D receptor agonist used, hence the subgroup analysis was not performed. The length of the follow-up period could be another factor leading to bias as only 3 studies11,16,19 had long-term follow-up (24 weeks). Other factors could have played a role in some of the findings as well, such as a short term change in GFR being a reflection of better blood pressure control rather a specific effect on diabetic nephropathy. Another limitation was an underrepresentation of type 1 DM, with only 1 study examining this group.15 Finally, not all studies could be included in the forest plot because of incomplete data.12,17 In conclusion, use of vitamin D and its analogues may have a role as an adjuvant therapy for reducing albuminuria and slowing progression of diabetic nephropathy though our findings in this meta-analysis of 9 RCTs did not reach statistical significance and further studies including ones using different forms and doses of vitamin D and its analogues are needed.
SUPPLEMENTARY MATERIALS Supplementary material associated with this article can be found, in the online version, at https://doi.org/ 10.1016/j.amjms.2018.12.005.
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REFERENCES 1. World Health Organization. Global Report on Diabetes. World Health Organization; 2016. 2. Gross JL, De Azevedo MJ, Silveiro SP, et al. Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care. 2005;28:164–176. 3. Hou FF, Zhang X, Zhang GH, et al. Efficacy and safety of benazepril for advanced chronic renal insufficiency. N Engl J Med. 2006;354:131–140. 4. Russo D, Minutolo R, Pisani A, et al. Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy. Am J Kidney Dis. 2001;38:18–25. 5. Cetinkaya R, Odabas AR, Selcuk Y. Anti-proteinuric effects of combination therapy with enalapril and losartan in patients with nephropathy due to type 2 diabetes. Int J Clin Pract. 2004;58:432–435. 6. Tan F, Mukherjee JJ, Lee KO, et al. Dual blockade of the renin-angiotensin-aldosterone system is safe and effective in reducing albuminuria in Asian type 2 diabetic patients with nephropathy. Singap Med J. 2010;51:151. 7. Takiishi T, Gysemans C, Bouillon R, et al. Vitamin D and diabetes. Endocrinol Metab Clin North Am. 2010;39:419–446. 8. Schwarz U, Amann K, Orth SR, et al. Effect of 1, 25 (OH) 2 vitamin D3 on glomerulosclerosis in subtotally nephrectomized rats. Kidney Int. 1998;53:1696–1705. 9. Freundlich M, Quiroz Y, Zhang Z, et al. Suppression of renin−angiotensin gene expression in the kidney by paricalcitol. Kidney Int. 2008;74:1394–1402. 10. Mizobuchi M, Morrissey J, Finch JL, 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;18:1796–1806. 11. De Zeeuw D, Agarwal R, Amdahl M, 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;376:1543–1551. 12. Krairittichai U, Mahannopkul R, Bunnag S. An open label, randomized controlled study of oral calcitriol for the treatment of proteinuria in patients with diabetic kidney disease. J Med Assoc Thai. 2012;95:S41–S47. 13. Ahmadi N, Mortazavi M, Iraj B, et al. Whether vitamin D3 is effective in reducing proteinuria in type 2 diabetic patients? J Res Med Sci. 2013;18:374. 14. Mustafar R, Mohd R, Miswan NA, et al. The effect of calcium with or without calcitriol supplementation on renal function in patients with hypovitaminosis d and chronic kidney disease. Nephrourol Mon. 2014;6: e13381.
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15. Joergensen C, Tarnow L, Goetze JP, et al. Vitamin D analogue therapy, cardiovascular risk and kidney function in people with type 1 diabetes mellitus and diabetic nephropathy: a randomized trial. Diabet Med. 2015;32:374–381. € Usalan C, Sayiner ZA. Vitamin D receptor activation with cal16. Tiryaki O, citriol for reducing urinary angiotensinogen in patients with type 2 diabetic chronic kidney disease. Ren Fail. 2016;38:222–227. 17. Jiang WJ, Zhang JA. Calcitriol reduces proteinuria and improves bone mineral density in patients with diabetic nephropathy: a prospective randomized controlled study. Int J Clin Exp Med. 2017;10:13194–13200. 18. Momeni A, Mirhosseini M, Kabiri M, et al. Effect of vitamin D on proteinuria in type 2 diabetic patients. J Nephropathol. 2017;6:10. 19. Liyanage PL, Lekamwasam S, Weerarathna TP, et al. Effect of vitamin D therapy on urinary albumin excretion, renal functions, and plasma renin among patients with diabetic nephropathy: a randomized, doubleblind clinical trial. J Postgrad Med. 2018;64:10. 20. Wolf G. New insights into the pathophysiology of diabetic nephropathy: from haemodynamics to molecular pathology. Euro J Clin Invest. 2004;34:785–796. 21. Balakumar P, Arora MK, Reddy J, et al. Pathophysiology of diabetic nephropathy: involvement of multifaceted signalling mechanism. J Cardiovasc Pharmacol. 2009;54:129–138. lez JF, Mora-Ferna ndez C, De Fuentes MM, et al. 22. Navarro-Gonza Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol. 2011;7:327. 23. Halimi JM. The emerging concept of chronic kidney disease without clinical proteinuria in diabetic patients. Diabetes Metab. 2012;38:291–297.
24. Ketteler M, Elder GJ, Evenepoel P, et al. Revisiting KDIGO clinical practice guideline on chronic kidney disease—mineral and bone disorder: a commentary from a kidney disease: improving global outcomes controversies conference. Kidney Int. 2015;87:502–508. 25. Ajabshir S, Asif A, Nayer A. The effects of vitamin D on the renin-angiotensin system. J Nephropathol. 2014;3:41. 26. Chen L, Kim SM, Eisner C, et al. Stimulation of renin secretion by angiotensin II blockade is Gsa-dependent. J Am Soc of Nephrol. 2010;21:986– 992. 27. Bischoff-Ferrari HA, Giovannucci E, Willett WC, et al. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr. 2006;84:18–28. 28. Bhan I, Dobens D, Tamez H, et al. Nutritional vitamin D supplementation in dialysis: a randomized trial. Clin J Am Soc Nephrol. 2015;10:611–619. 29. Banerjee S, Basu S, Sen A, et al. The effect of vitamin D and calcium supplementation in pediatric steroid-sensitive nephrotic syndrome. Pediatr Nephrol. 2017;32:2063–2070.
Submitted July 20, 2018; accepted December 11, 2018. Conflicts of Interest: Authors declare no conflicts of interest. Grant/Fund support: None. Correspondence: Sonali Gupta, MD, Department of Medicine, St. Vincent’s Medical Center, 2800 Main Street, Bridgeport, CT, 06606. (E-mail: [email protected]).
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Role of Vitamin D and Its Analogues in Diabetic Nephropathy: A Meta-analysis D1X XSonali Gupta, D2X XMD1,2, D3X XPradeep Goyal, D4X XMD2,3, D5X XRichard S. Feinn, D6X XPhD4 and D7X XJoseph Mattana, D8X XMD1,2 1
Department of Medicine, St. Vincent’s Medical Center, Bridgeport, Connecticut; The Frank H. Netter MD School of Medicine at Quinnipiac University, North Haven, Connecticut; 3 Department of Radiology, St. Vincent’s Medical Center, Bridgeport, Connecticut; 4 Department of Medical Sciences, The Frank H. Netter MD School of Medicine at Quinnipiac University, North Haven, Connecticut
2
ABSTRACT Background: Diabetic nephropathy remains one of the most common causes of chronic kidney disease in the United States and is associated with significant morbidity and mortality. Recently, there have been emerging data highlighting the role of vitamin D and its analogue in chronic kidney disease especially diabetic nephropathy independent of its effect on bone metabolism. Methods: This study aimed to evaluate effect of supplementing vitamin D and its analogues on halting or slowing progression of diabetic nephropathy. Electronic databases (PubMed, Scopus, Google scholar) were searched and randomized controlled trials (RCTs) that investigated the use of vitamin D and its analogs for diabetic nephropathy were studied. This meta-analysis of RCTs performed in accordance with Preferred Reporting Items for Systematic review and Meta-analysis statement. Results: This meta-analysis included 9 RCTs and suggested a favorable trend with respect to an effect of vitamin D and its analogues on albuminuria though this did not reach statistical significance (MD, ¡0.17; 95% CI, ¡0.34-0.01; P = 0.06]. Serum calcium was unaffected suggesting safe use of these agents. Conclusions: Use of vitamin D and its analogues may have potential as an adjuvant therapy for reducing albuminuria and slowing progression of diabetic nephropathy but further studies are needed. Key Indexing Terms: Diabetic nephropathy; Chronic kidney disease; Vitamin D. [Am J Med Sci 2019;357(3):223−229.]
INTRODUCTION
T
he prevalence of diabetes mellitus (DM) has been increasing rapidly over the last 3 decades. Globally, the number of people affected by DM has steadily increased from 108 million in 1980 to 422 million in 2014.1 Diabetic nephropathy is the most common cause of chronic kidney disease in the United States and is found to affect at least 40% of patients with DM.2 It is associated with high cardiovascular mortality2 and there are an estimated 1.6 million deaths every year directly attributed to DM.1 In addition to strategies to prevent DM and diabetic nephropathy it is important that strategies to slow the progression of diabetic nephropathy are begun at the earliest possible time. Drugs targeting the renin angiotensin system (RAS) have become the mainstay of efforts to slow the progression of diabetic nephropathy given the critical role of the RAS in its pathogenesis and progression.3-6 A limitation of RAS targeted therapies such as angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) is a compensatory rise in renin production which
may attenuate the efficacy of RAS inhibition. Hence in addition to drugs targeting the RAS there is a need for additional therapies to help slow the progression of diabetic nephropathy. Vitamin D deficiency has been reported to be associated with the development of type 1 and type 2 DM and diabetic nephropathy.7 Recent clinical and experimental data have highlighted a potential renoprotective effect of vitamin D and its analogs independent of their action on calcium and phosphorus metabolism.8-10 The mechanism by which vitamin D and its analogs may accomplish this is not clearly understood. The aim of this meta-analysis is to evaluate the potential role of vitamin D and its analogues as a therapy for diabetic nephropathy and to summarize the available evidence.
METHODS Search Strategy Electronic databases (PubMed, Scopus, Google scholar) were searched and interventional studies that investigated the use of vitamin D and its analogs for diabetic nephropathy
Copyright © 2019 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved. www.amjmedsci.com www.ssciweb.org
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were studied. All the published articles till January 2018 were included. The search terms used were "vitamin D," "cholecalciferol," "calcitriol," "alfacalcidol," "paricalcitol," "diabetic nephropathy," "diabetic kidney disease,” "albuminuria," "proteinuria," "chronic kidney disease" and "diabetes." Boolean operators were used to combine all searches. Additional studies were added after checking the reference lists of all related publications. Inclusion and Exclusion Criteria Interventional studies that met the following criteria were included in this meta-analysis: (i) patients 18 years or older with diagnosed diabetic nephropathy; (ii) the interventions in the studies including supplementation with vitamin D3 or its analogs; (iii) albuminuria including microor macroalbuminuria; (iv) randomized controlled trial design and (v) published in the English language. Major exclusion criteria were as follow: (i) case reports, case series, letter to editors and review articles; (ii) studies whose full text could not be assessed or those with incomplete data; (iii) studies without a placebo group, observational or cross sectional studies and (iv) animal studies. Two reviewers reviewed all the literature searches and determination of eligible studies was finalized. Disagreement between the 2 reviewers was resolved through consensus or referring to a third reviewer. This meta-analysis was performed according to Preferred Reporting Items for Systematic review and Meta-analysis statement. Outcomes and Data Extraction The outcomes studied included urine albumin creatinine ratio (UACR), urine protein creatinine ratio, 24-hour urine protein excretion, urinary albumin excretion rate (UAER) and change in serum 25 (OH) vitamin D, serum 1,25 (OH) vitamin D, creatinine, calcium and parathyroid hormone (PTH). The extracted information included study design, number of participants, baseline characteristics (including age, sex, type of DM), type of interventions (including type and dose of vitamin D and therapy duration and frequency) and outcome measures. Two authors (SG and PG) independently performed data extraction and disagreements were resolved by consensus or by referring to a third author (JM). Statistical Analysis This meta-analysis was conducted to perform direct comparisons between the intervention and placebo. Review Manager Software (RevMan V5.3, 2014, Cochrane Collaboration, United Kingdom) was used for data analysis and preparing the article. The effect measures in meta-analysis were reported as the percent change (%) in the mean difference, 95 % confidence interval (CI) and their standard deviations. The mean difference and standard deviations were used for the visual representation of results in the forest plots. Interstudy heterogeneity was evaluated by the I2 test and when 224
I2 > 50%, random effect model was used, otherwise, fixed effects model was adopted. Funnel plot was used to assess potential publication bias. P < 0.05 was considered statistically significant. Quality Assessment and Risk of Bias Quality assessments of the included studies were done using Review Manager V 5.3, 2014 (Cochrane Collaboration, United Kingdom). Included studies were assessed on the basis of randomization, allocation concealment, blinding process, selective reporting and outcome measurement. Two reviewers (SG and PG) independently performed this analysis and disagreement between the 2 reviewers was resolved through consensus or referring to a third reviewer (JM).
RESULTS Search Results The search strategy resulted in a total of 381 studies from PubMed, Scopus and Google Scholar. Thirty-four studies remained for further screening after removal of duplicates and review of titles and abstracts by 2 reviewers. Among these studies, 25 studies were further excluded due to different languages of the article, nonrandomized design, being an animal study and measurement of different outcome. Nine RCTs were ultimately included in the analysis (Figure 1).11-19 Characteristics of Included Studies Of the 9 included studies, 1 was multinational,11 1 was performed in Europe,15 1 in China,17 1 in Thailand,12 1 in Malaysia,14 1 in Sri Lanka,19 2 in Iran13,18 and 1 in Turkey.16 One study included only patients with type 1 diabetes,15 1 study did not mention the type of diabetics included19 and the rest included patients with type 2 DM.11-14,16-18 At baseline, the studies included 734 patients (369 patients who received vitamin D and 365 who received placebo). Four studies used calcitriol in interventional group,12,14,16,17 2 studies used paricalcitol,11,15 1 study used cholecalciferol,13 1 study mentions use of vitamin D319 and 1 study did not specify the type of vitamin D used.18 The primary outcomes measured were as follows: percent change in UACR (5 studies),11,13,16,17,19 change in UAER (2 studies),11,15 change in 24-hour urine protein excretion (1 study)18 and urine protein creatinine index (UPCI, 2 studies).12,14 Other parameters measured were change in levels of calcium, serum creatinine, PTH, 25 (OH) vitamin D and 1.25 (OH) vitamin D. Mean duration of treatment varied from 6 weeks to 6 months. Table 1 summarizes the baseline characteristics of the patients in the included studies. Main Results The studies were grouped on the basis of the outcome measured to avoid errors and misinterpretation. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES VOLUME 357 NUMBER 3 MARCH 2019
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Articles identiied from all sources (n= 381)
Articles after removing duplicates (n= 186) Articles excluded by screening of title and abstract (n= 152) Potentially relevant articles identiied and screened for retrieval (n=34) Excluded (n=25); Language not English (n= 12), Not RCT (n=4), animal study (n=1), Outcome measured different (n=8)
RCT included in meta-analysis (n=9) FIGURE 1. Literature search flow charts. Abbreviation: RCT, randomized controlled trial.
UAER was evaluated in 2 studies.11,15 No statistically significant change in UAER was found with vitamin D therapy (mean difference, ¡0.18; 95% CI, ¡0.43 to 0.06; P = 0.14; Figure 2). Five studies evaluated change in UACR following vitamin D therapy.11,13,16,17,19 One study could not be used in the forest plot because of missing data.16 The overall result for the remaining studies favored use of a vitamin D analogue to reduce albuminuria though this did not quite reach statistical significance [mean difference, ¡0.17; 95% CI, ¡0.34 to 0.01; P = 0.06]. There was no heterogeneity between trials (I2= 0%, P =0.95, Figure 3). Two studies evaluated UPCI,14,18 however one of these could not be used because of incomplete crude data for analysis.12 The study of Mustafar et al14 showed no significant change in proteinuria as determined by UPCI regardless of diabetes status (mean difference, ¡0.19; 95% CI, ¡0.90 to 0.51; P = 0.59) as shown in Figure 4. The other secondary outcome measured was change in serum creatinine. Pooled data from the included studies showed no statistically significant change in serum creatinine in both groups (mean difference, ¡0.15; 95% CI, ¡0.62 to 0.2, P = 0.53) though the groups showed moderate heterogeneity (I2 57%, P = 0.10, Supplementary Figure 1). Change in serum PTH, calcium and 1,25 (OH) vitamin D levels also did not reach significance (PTH: mean difference, 0.06, 95% CI, ¡0.21, 0.33, P = 0.66; calcium: mean difference, 0.08, 95% CI, ¡0.04, 0.19, P = 0.19; 1,25(OH) vitamin D: mean difference, 0.53, 95% CI ¡0.46, 1.53, P = 0.29) as shown in Supplementary Figures 2-4. However, 25 (OH) vitamin D levels differed significantly in the 2 groups and reached statistical significance (P < 0.05) as shown in Supplementary Figure 5. Subgroup analysis on the basis of the different
vitamin D receptor agonist used could not be performed because of the small number of studies. Quality Assessment of Included Studies There was great variation in the overall quality of the studies included in the analysis. The studies varied in their design, methodology, duration of intervention and primary outcome measure. Overall risk of selection bias was low as baseline characteristics of the groups were similar at the beginning of the studies although attrition bias was high as 5 studies did not mention follow-up results.11,13,15,17,18 Methods for randomization and blinding are not reported in 4 RCTs12,14,17,18 thereby resulting in high performance bias. Figure 5 shows risk bias and Table 2 shows quality assessments of the included studies. Funnel plot was used to assess potential publication bias of the included studies. No statistical significance in the 7 outcomes was found (all P values > 0.05, Supplementary Figure 6).
DISCUSSION Diabetic nephropathy is the result of complex interaction between genetic, environmental, metabolic, hemodynamic and vasoactive factors.20-22 Hyperglycemia triggers a cascade of metabolic events including activation of proinflammatory cytokines, oxidative stress induction, polyol and hexosamine influx and production of advanced glycated endproducts (AGEs). AGEs are resistant to enzymatic hydrolysis by matrix metalloproteinase and thereby accumulate leading to glomerular basement membrane thickening and mesangial expansion. AGEs also interact with receptors for AGEs leading to generation of oxygen radicals and other sequelae.
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UACR (mg/mmol) UPCR (g/g) UPCI (g/mmol) UACR (mg/g) UACR (units not mentioned) 24 hours proteinuria (mg/day) Abbreviation: MN, Multinational; UA,Urinary albumin; UACR, Urinary albumin/Creatinine ratio; UAER, Urinary albumin excretion rate; UPCR,Urinary protein/Creatinine rate.
12 weeks 16 weeks 12 weeks 6 months 12 weeks 8 weeks 6 weeks UAER (mg/24 hour) Paricalcitol 1-2 mg once daily 56.1 52.8 Calcitriol 0.25 mg once daily 59.7 61.8 Calcitriol 0.25-0.5 mg twice weekly 55 52 Calcitriol 0.5 mg daily 56 59 Vitamin D3 50,000IU monthly 58.3 57.1 Cholecalciferol 50,000IU/weeks 62.9 62.4 Vitamin D 50,000IU weekly 56 40 37.8 52 42.9 30.4 40 66.6 46.6 56.5 64 48.8 42.9 60 24 30 46 25 42 30 30 Type 1 Type 2 Type 2 Type 2 NA Type 2 Type 2
24 30 45 25 43 30 30
24 weeks 2 mg once daily 95 Type 2
93
73
65
65
64
Paricalcitol
24 weeks 1 mg once daily Paricalcitol 64 64 65 71 93 93 Type 2
De Zeeuw 2010 MN (low dose) De Zeeuw 2010 MN (high dose) Joergensen 2015 Europe Jiang 2017 China Krairittichai 2012 Thailand Mustafar 2014 Malaysia Liyanage 2018 Sri Lanka Ahmadi 2013 Iran Momeni 2017 Iran
C I C
Male sex (%)
I C
Sample size
Type of diabetes Country Study
TABLE 1. Baseline characteristics of included studies.
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I
Mean age (years)
Supplement form
Dosage
Duration of treatment
End point
24 hours UA (mg) UACR (mg/mmol) 24 hours UA (mg), UACR (mg/mmol)
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Hyperglycemia also influences the local renal RAS resulting in increased production of angiotensin II, which in turn causes elevation of intraglomerular pressure by preferential constriction of the efferent arteriole. Hemodynamic changes including hyperfiltration and increased glomerular perfusion are evident earlier in the course of diabetic nephropathy, well before clinical signs of renal damage are evident. Structural changes aside from glomerular basement membrane thickening and mesangial expansion include podocyte foot process effacement and disruption of the dynamic filtration barrier as a result of decreased expression and increased excretion of podocyte and slit diaphragm proteins. In addition, various growth factors are activated resulting in renal inflammation, cell growth, fibrosis, mitogenesis, differentiation, migration and apoptosis. Ultimately, these molecular changes result in glomerulosclerosis, proteinuria, tubulointerstitial fibrosis, hyalinosis and arteriosclerosis of renal vessels. The classical natural history of diabetic nephropathy consists of an early stage of microalbuminuria followed by an increase in proteinuria and progressive decline in the glomerular filtration rate. However, recent studies have shown that disease progression can differ from this model as there can be a significant deterioration in the glomerular filtration rate early in the course of diabetic nephropathy irrespective of proteinuria.23 In our meta-analysis, we have included studies which have defined diabetic nephropathy by the presence of microalbuminuria and hence our findings may not be applicable for forms of diabetic kidney disease which are nonproteinuric. Treatment with RAS inhibitors has had a major impact on diabetic nephropathy though there is a need for additional therapies. While vitamin D supplementation has become part of clinical practice guidelines for the management of abnormal bone metabolism in chronic kidney disease24 its potential role as a therapy to modulate the course of diabetic nephropathy has been less well studied until more recently.11-19 The antiproteinuric effect of vitamin D and its analogs is thought to be secondary to inhibition of renin25 though RCTs evaluating the effect of vitamin D supplementation on renin are limited. Of note, despite their antiproteinuric effect, ACEIs and ARBs lead to an increase in renin secretion26 which may offset some of their beneficial actions in diabetic nephropathy. Liyanage et al have reported a gradient of microalbuminuria suppression across levels of serum renin concentrations.19 Given that therapy with ACEIs and ARBs increases renin this suggests that vitamin D supplementation might serve as a helpful adjunct to RAS-based antiproteinuric therapy. Also of note efficacy of ACEIs and ARBs may be limited by failure to follow a low sodium diet. Paricalcitol has been shown to reduce albuminuria irrespective of dietary sodium intake19 further suggesting that vitamin D therapy might be of benefit as an addition to RAS-based treatment regimens for diabetic nephropathy. It is also worth emphasizing that in studies evaluating the effect of vitamin D (or any other THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES VOLUME 357 NUMBER 3 MARCH 2019
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FIGURE 2. Forest plot of urinary albumin excretion rate (UAER) change in patients with diabetic nephropathy (DN).
FIGURE 3. Forest plot of urinary albumin creatinine ratio (UACR) change in patients with diabetic nephropathy (DN).
FIGURE 4. Forest plot of urinary protein creatinine ratio (UPCR) change in patients with diabetic nephropathy (DN).
FIGURE 5. Risk bias assessment of included studies.
agent) when added to an ACEI or ARB, the ACE/ARB dosing should be stable throughout the study period to help separate out an effect of the intervention (in this case vitamin D or an analog) from the ACEI or ARB. While many of the included studies in our meta-analysis clearly mention the number of patients on stable doses of ACEI/ ARBs,11,12,14,15,16 data were missing from several others.13,17,18,19 Appropriate dosage and duration of therapy with vitamin D and its analogs for a maximum antiproteinuric effect is uncertain. There is a pleiotropic effect of vitamin D receptor agonists on metabolism, inflammation and the immune system, which has gained attention and requires consideration of a potentially fine balance between beneficial and adverse effects. Bischiff-Ferrari
et al reported health benefits of vitamin D when 25(OH) vitamin D levels reached 75 nmol/L.27 The DIVINE study concluded ergocalciferol supplementation to be safe and without significant effect on blood calcium, phosphate or PTH hormone levels in incident hemodialysis patients.28 Liyanage et al reported supernormal levels of 25(OH) vitamin D (81.75 nmol/L in the intervention group) without adverse effects.19 However, Banerjee et al reported hypercalciuria in 52% of patients in intervention group emphasizing caution and a need for regular follow-up.29 Our meta-analysis showed a significant increase in 25 (OH) vitamin D levels without a significant increase in serum calcium in the intervention group suggesting vitamin D and its analogue may be safe to use in diabetic nephropathy. However, variation in study design,
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TABLE 2. Quality assessment of included studies. Studies Sample sizea Randomization Randomization methodb Allocation concealment Participant blinded Outcome measure (valid/reliable) Assessor blinded Equal follow-upc Attrition rate equal for both groups Completenessd Groups similar at baselines
De Zeeuw
Joergensen
Jiang
Krairttichai
Mustafar
Liyanage
Ahmadi
Monemi
Tiyakari
+ + + + + + + ¡ ¡ + +
+ + + + + + + ¡ ¡ + +
+ + ¡ ¡ ¡ + ¡ ¡ ¡ + +
+ + ¡ ¡ ¡ + ¡ + + + +
+ + ¡ ¡ ¡ + ¡ + + + +
+ + + + + + + + + + +
+ + + ¡ + + + ¡ ¡ + +
+ + ¡ ¡ ¡ + ¡ ¡ ¡ + +
+ + + ¡ ¡ + ¡ + + + +
Notes: (+) indicates that the measure was adequately addressed in the study. (¡) indicates that the factor was not measured, or not adequately addressed in the study. a Studies receives (+) if sample size was justified. b Studies received (+) if randomization method was specified in the study and (¡) if no method was specified. c Studies received (+) if groups were followed within 10% of each other or for the same time. d Studies received (+) if full description of those lost to follow-up was mentioned and final analysis included >80% of population.
intervention and small sample size limit generalization of the results. While our meta-analysis suggested a trend toward a favorable effect of vitamin D and its analogues on albuminuria in diabetic nephropathy our findings did not quite reach statistical significance (P = 0.06). The main strength of this study is that it is a meta-analysis of all the RCTs evaluating the effect of vitamin D receptor agonists on diabetic nephropathy. However, there were several limitations in this study. First, there is heterogeneity of data particularly in a handful of studies as regards the basis of primary outcome and vitamin D receptor agonist used, hence the subgroup analysis was not performed. The length of the follow-up period could be another factor leading to bias as only 3 studies11,16,19 had long-term follow-up (24 weeks). Other factors could have played a role in some of the findings as well, such as a short term change in GFR being a reflection of better blood pressure control rather a specific effect on diabetic nephropathy. Another limitation was an underrepresentation of type 1 DM, with only 1 study examining this group.15 Finally, not all studies could be included in the forest plot because of incomplete data.12,17 In conclusion, use of vitamin D and its analogues may have a role as an adjuvant therapy for reducing albuminuria and slowing progression of diabetic nephropathy though our findings in this meta-analysis of 9 RCTs did not reach statistical significance and further studies including ones using different forms and doses of vitamin D and its analogues are needed.
SUPPLEMENTARY MATERIALS Supplementary material associated with this article can be found, in the online version, at https://doi.org/ 10.1016/j.amjms.2018.12.005.
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15. Joergensen C, Tarnow L, Goetze JP, et al. Vitamin D analogue therapy, cardiovascular risk and kidney function in people with type 1 diabetes mellitus and diabetic nephropathy: a randomized trial. Diabet Med. 2015;32:374–381. € Usalan C, Sayiner ZA. Vitamin D receptor activation with cal16. Tiryaki O, citriol for reducing urinary angiotensinogen in patients with type 2 diabetic chronic kidney disease. Ren Fail. 2016;38:222–227. 17. Jiang WJ, Zhang JA. Calcitriol reduces proteinuria and improves bone mineral density in patients with diabetic nephropathy: a prospective randomized controlled study. Int J Clin Exp Med. 2017;10:13194–13200. 18. Momeni A, Mirhosseini M, Kabiri M, et al. Effect of vitamin D on proteinuria in type 2 diabetic patients. J Nephropathol. 2017;6:10. 19. Liyanage PL, Lekamwasam S, Weerarathna TP, et al. Effect of vitamin D therapy on urinary albumin excretion, renal functions, and plasma renin among patients with diabetic nephropathy: a randomized, doubleblind clinical trial. J Postgrad Med. 2018;64:10. 20. Wolf G. New insights into the pathophysiology of diabetic nephropathy: from haemodynamics to molecular pathology. Euro J Clin Invest. 2004;34:785–796. 21. Balakumar P, Arora MK, Reddy J, et al. Pathophysiology of diabetic nephropathy: involvement of multifaceted signalling mechanism. J Cardiovasc Pharmacol. 2009;54:129–138. lez JF, Mora-Ferna ndez C, De Fuentes MM, et al. 22. Navarro-Gonza Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol. 2011;7:327. 23. Halimi JM. The emerging concept of chronic kidney disease without clinical proteinuria in diabetic patients. Diabetes Metab. 2012;38:291–297.
24. Ketteler M, Elder GJ, Evenepoel P, et al. Revisiting KDIGO clinical practice guideline on chronic kidney disease—mineral and bone disorder: a commentary from a kidney disease: improving global outcomes controversies conference. Kidney Int. 2015;87:502–508. 25. Ajabshir S, Asif A, Nayer A. The effects of vitamin D on the renin-angiotensin system. J Nephropathol. 2014;3:41. 26. Chen L, Kim SM, Eisner C, et al. Stimulation of renin secretion by angiotensin II blockade is Gsa-dependent. J Am Soc of Nephrol. 2010;21:986– 992. 27. Bischoff-Ferrari HA, Giovannucci E, Willett WC, et al. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr. 2006;84:18–28. 28. Bhan I, Dobens D, Tamez H, et al. Nutritional vitamin D supplementation in dialysis: a randomized trial. Clin J Am Soc Nephrol. 2015;10:611–619. 29. Banerjee S, Basu S, Sen A, et al. The effect of vitamin D and calcium supplementation in pediatric steroid-sensitive nephrotic syndrome. Pediatr Nephrol. 2017;32:2063–2070.
Submitted July 20, 2018; accepted December 11, 2018. Conflicts of Interest: Authors declare no conflicts of interest. Grant/Fund support: None. Correspondence: Sonali Gupta, MD, Department of Medicine, St. Vincent’s Medical Center, 2800 Main Street, Bridgeport, CT, 06606. (E-mail: [email protected]).
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