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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2012  |  Volume : 23  |  Issue : 6  |  Page : 1215-1220
The effects of calcitriol on albuminuria in patients with type-2 diabetes mellitus


1 Endocrine Research Center, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
2 Kidney Transplantation Complications Research Center, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
3 Department of Internal Medicine, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran

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Date of Web Publication17-Nov-2012
 

   Abstract 

The renin-angiotensin system has a major role in the development of diabetic nephropathy (DN). It is reported that vitamin D analogues are able to suppress renin excretion. Thus, this study was conducted to determine whether there is any correlation between albuminuria as a marker of DN with vitamin D levels in diabetic patients. Also, an assessment was made on the effects of vitamin D therapy on albuminuria in this group of patients. We conducted this cross-sectional study on 119 outpatients with type-2 diabetes. The serum levels of 25-hydroxy vitamin D [25 (OH) D] and the albumin to creatinine ratio were assessed in all the study patients. Patients with vitamin D deficiency/insufficiency received calcitriol therapy for eight weeks, following which the laboratory tests were repeated. The mean age of the study patients was 55.3 ± 11.2 years, 43 (36.13%) had vitamin D insufficiency [25 (OH) D <25 ng/mL] and 31 (26.1%) had vitamin D deficiency [25 (OH) D <15 ng/mL]. We found a significant correlation between 25 (OH) D levels and presence of microalbuminuria (P = 0.04) in patients with vitamin D deficiency. Therapy with calcitriol had a beneficial effect on the albumin excretion rate, although this change was not significant (P = 0.22). However, the effects of calcitriol on reduction of diastolic blood pressure (P = 0.004), glycosylated hemoglobin (P = 0.014) and levels of total cholesterol (P = 0.019), low-density lipoprotein (0.04) and high-density lipoprotein (P = 0.001) was significant. Our study suggests that vitamin D deficiency has a negative effect on albuminuria in diabetic patients, and its replacement may be associated with a beneficial effect on the risk factors of DN, such as hyperlipidemia and hypertension.

How to cite this article:
Bonakdaran S, Hami M, Hatefi A. The effects of calcitriol on albuminuria in patients with type-2 diabetes mellitus. Saudi J Kidney Dis Transpl 2012;23:1215-20

How to cite this URL:
Bonakdaran S, Hami M, Hatefi A. The effects of calcitriol on albuminuria in patients with type-2 diabetes mellitus. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2014 Sep 1];23:1215-20. Available from: http://www.sjkdt.org/text.asp?2012/23/6/1215/103562

   Introduction Top


Diabetes mellitus (DM) is a rapidly growing health problem in developing countries. [1] In Iran, about 10% of the general population had DM or impaired fasting glucose in 2008. [2] Diabetic nephropathy (DN) is the most common complication of DM, and is a leading cause of end-stage renal disease presently. [3] Systemic and local (intra-renal) renin-angiotensin system (RAS) plays a critical role in the development and progression of DN; [4] thus, treatment with angio-tensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) may be beneficial. It has been reported that the usage of these drugs is associated with compensatory increase in the intra-renal renin levels. [5]

In animal studies, it has been reported that vitamin D analogs are able to suppress renin expression, [6] inhibition of mesangial cell proliferation, [7] reduction of glomerulosclerosis and expression of fibrogenic markers. [8] Zhang et al found that combination therapy with AT1 blocker and vitamin D analogues markedly ameliorates DN. [9]

In previous human studies, the prevalence of albuminuria was enhanced with decreased levels of 25-hydroxy vitamin D [25 (OH) D] [10] and newer vitamin D analogues such as paricalcitriol, reduced albuminuria and inflammation in patients with chronic kidney disease (CKD). [11] Vitamin D deficiency is common worldwide, especially in diabetic patients, [12] and it may be related to hypertension, [13] metabolic syndrome, [14] insulin resistance [15] and cardiovascular disease (CVD), all of which worsen albuminuria. We then tried to assess the effect of calcitriol therapy on albuminuria in type-2 diabetic patients with vitamin D deficiency.


   Materials and Methods Top


Participants

Patients from the diabetes clinic at the Ghaem Hospital, Mashhad, Iran, were recruited between February and June 2009. They were considered eligible for the study if they had type-2 diabetes according to the World Health Organization definition.

Patients with history of acute illness, infection, malignancy, malabsorption, alcoholism, smoking, chronic liver disease and renal failure and those who were taking medications that interfere with measurement of 25 (OH) D level (glucocorticosteriods, anti-convulsants, vitamin D and calcium products) were excluded.

Study design

This study was designed as a cross-sectional and interventional study. After obtaining a detailed medical history and performing a physical examination, we measured the blood pressure and body mass index (BMI) on all patients. The BMI was calculated by dividing weight in kg by height in m 2 . The blood pressure was measured after 30 min resting with a standard mercury manometer. Blood samples were collected after an overnight fasting and analyzed for fasting blood pressure (FBS), lipid profile, glycosylated hemoglobin (HbA1C), high-sensitive C-reactive protein (HS-CRP) and 25 (OH) D, and random spot urine was tested for the albumin to creatinine ratio (ACR). Patients were defined as being vitamin D deficient and insufficient if the serum 25 (OH) D level was less than 15 ng/mL and 25 ng/mL, respectively. All patients with vitamin D insufficiency/deficiency were instructed to take calcitriol therapy. These patients were treated with 0.5 μg calcitriol daily for eight weeks. At the end of the treatment period, all the baseline clinical and laboratory markers were repeated.

The FBS was measured by the glucose oxidase method (Human, Germany). The total cholesterol, triglyceride and HDL were measured by an enzymatic method (Parsazmon Karaj, Iran). The LDL was calculated according to Friedwall's formula in subjects with triglyceride level less than 300 mg/dL [LDL = total cholesterol - (HDL + tg / 5)]. The level was assessed by column chromatography (Biosource kit, Barcelona, Spain). The HS-CRP concentration was measured by immuno-turbidometry assay (Parsazmon). Serum concentration of 25 (OH) D was measured by the radio immunoassay method (Biosource Europ, Nivelles, Belgium). Urinary albumin was measured as the ACR in a morning sample by immunoturbidometry assay (Parsazmon). Urine creatinine was measured by an enzymatic colorimetric assay.


   Statistical Analysis Top


Data are expressed as mean ± SD. Statistical analysis was done by paired t test for normally distributed variables and by Kruskal Wallis test for comparison of not normally distributed data before and after treatment. Pearson correlation coefficients and Spearman were compared to quantify the correlation of vitamin D and other variants. A P-value <0.05 was considered significant. All patients gave informed voluntary consent and the study protocol was approved by the research ethics committee of MUMS (Mashhad University of Medical Sciences).


   Results Top


A total of 150 patients were assessed for eligibility of the study, of whom 31 patients were excluded; the remaining 119 were enrolled into the study. The mean serum level of 25 (OH) D was 30.42 ± 21.7 ng/mL. Thirty-one patients (26.1%) had vitamin D deficiency, most of whom were female. When patients with normal vitamin D levels and those with vitamin D deficiency were compared, no significant correlation was found with gender, age, duration of diabetes and calcium and phosphorous levels; however, there was a significant correlation between BMI, HS-CRP, ACR, glomerular filtration rate and 25 (OH) D levels [Table 1].
Table 1: Baseline characteristics according to vitamin D status (N = 119).

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Forty-three patients (36.13%) had vitamin D insufficiency/deficiency, and they were treated with vitamin D supplement. The supplement was generally well tolerated and only one patient discontinued treatment, which was due to hospitalization for angina pectoris.

Following treatment of vitamin D-insufficient patients with 0.5 μg calcitriol daily for eight weeks, a significant reduction in diastolic blood pressure (P = 0.004), HbA1C (0.014), total cholesterol (P = 0.019), LDL (0.04) and HDL (P = 0.001) was noticed. Calcitriol had a beneficial effect on AER (P = 0.22), systolic blood pressure (P = 0.07), FBS (P = 0.16) and triglyceride (0.38), although these changes were not significant. The effect of treatment on variables is shown in [Table 2].
Table 2: Comparison of parameters in diabetic patients with vitamin D insufficiency before and after treatment with calcitriol.

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   Discussion Top


The key findings of this study are as follows:

  1. The prevalence of albuminuria was high in diabetic patients with low 25 (OH) D levels
  2. Short-term exposure to calcitriol results in significant improvement in diastolic blood pressure, HbA1C, total cholesterol and LDL
  3. A reduction in albuminuria was found after calcitriol therapy, but this change was not significant.
Our results regarding increased levels of albuminuria with decreasing vitamin D levels is consistent with several clinical studies that have reported that low 25 (OH) D levels was associated with an increased risk of albuminuria in diabetic and non-diabetic patients. [16],[17],[18] Direct cellular effects of vitamin D deficiency, including podocyte loss and increasing glomerulosclerosis, may be contributing to the increasing risk of albuminuria. [9] Despite biological plausibility, our study did not show a significant decrease in albuminuria after calcitriol therapy. Short duration of follow-up and small size of the study population may have been reasons for the insignificant reduction in albuminuria after calcitriol therapy in our study.

There is some evidence that describes the beneficial effect of vitamin D supplement therapy on regulation of blood pressure. Pfeifer et al [19] demonstrated that supplement therapy with calcium and vitamin D results in better reduction of systolic blood pressure compared with calcium alone. Other clinical studies have reported an inverse relation between vitamin D level and blood pressure. [20],[21],[22] Treatment with paricalcitol increases nitric oxide synthesis and cyclooxygenase expression that causes vasodilatation and reduces oxytocin receptor expression that promotes vasoconstriction. The effect of vitamin D on blood pressure may be related to suppression of renin formation by vitamin D or reduction of parathormone (PTH), which may reduce peripheral vascular resistance through a direct effect on vascular smooth vascular tone. [23] Suppression of RAS signaling by vitamin D is not related to its effect on calcium and PTH. [24] In our study, we found a significant correlation between vitamin D replacement therapy and only diastolic blood pressure, and there was no correlation between systolic blood pressure and this therapy. The major limitation in our study was that we relied on spot blood pressure measurement, although we know that 24-h BP monitoring is more reliable than spot measurement.

We found that supplement therapy with calcitriol caused a significant reduction in HbA1C, total cholesterol and LDL levels. The change in HbA1C is consistent with other studies that have reported a beneficial effect of vitamin D in delaying the progression of diabetes and also restoration of insulin secretion and improvement of insulin resistance. [25],[26] On the other hand, HDL-cholesterol significantly decreased after treatment. Heikkinen et al showed that long-term supplementation with vitamin D lowered HDL-cholesterol among post-menopausal women. [27] Wehmeier et al found that 1, 25 (OH) 2 D 3 suppresses ApoA1 gene expression, and we know that ApoA1 is the major apoprotein of HDL, and it seems that this phenomenon is a potential cause of decreased HDL concentration after treatment. [28]


   Limitations of the Study Top


  1. Small sample size and limited duration of exposure to drug
  2. 25 (OH) vitamin D levels were not measured after calcitriol therapy for estimation of adequacy of vitamin D treatment
  3. Lack of evaluation of PTH levels.
In summary, the present study found that there is a relation between albuminuria and vitamin D deficiency. Our results call for other studies to prove this association and to clarify the effect of vitamin D analogs on blood pressure and albuminuria. If these results confirm our findings and those of other studies, vitamin D supplementation could be important in maintaining renal and cardiac health.

 
   References Top

1.Haghdoost AA, Rezazadeh-Kermani M, Sadghirad B, Baradaran HR. Prevalence of type 2 diabetes in the Islamic Republic of Iran: systematic review and meta-analysis. East Mediterr Health J 2009;15:591-9.  Back to cited text no. 1
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2.Harati H, Hadaegh F, Saadat N, Azizi F. Population-based incidence of Type 2 diabetes and its associated risk factors: Results from a six-year cohort study in Iran. BMC Public Health. 2009;9:186.  Back to cited text no. 2
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3.Zelmanovitz T, Gerchman F, Balthazar AP, Thomazelli FC, Matos JD, Canani LH. Diabetic nephropathy. Diabetol Metab Syndr 2009;1:10  Back to cited text no. 3
    
4.Patel A, ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): A randomised controlled trial. Lancet 2007;370: 829-40  Back to cited text no. 4
    
5.Muller DN, Luft FC. Direct renin inhibition with aliskiren in hypertension and target organ damage. Clin J Am Soc Nephrol 2006;1:221-8.  Back to cited text no. 5
    
6.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.  Back to cited text no. 6
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7.Tan X, Li Y, Liu Y. Therapeutic role and potential mechanisms of active Vitamin D in renal interstitial fibrosis. J Steroid Biochem Mol Biol 2007;103:491-6.  Back to cited text no. 7
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8.Schwarz U, Amann K, Orth SR, Simonaviciene A, Wessels S, Ritz E. Effect of 1,25 (OH)2 Vitamin D3 on glomerulosclerosis in subtotally nephrectomized rats. Kidney Int 1998;53:1696-705.  Back to cited text no. 8
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9.Zhang Z, Zhang Y, Ning G, Deb DK, Kong J, Li YC. Combination therapy with AT1 blocker and Vitamin D analog markedly ameliorates diabetic nephropathy: Blockade of compensatory renin increase. Proc Natl Acad Sci U S A 2008;105:15896-901.  Back to cited text no. 9
    
10.De Boer IH, Ioannou GN, Kestenbaum B, Brunzell JD, Weiss NS. 25-HydroxyVitamin D levels and albuminuria in the Third National Health and Nutrition Examination Survey (NHANES III). Am J Kidney Dis 2007;50:69-77.  Back to cited text no. 10
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11.Alborzi P, Patel NA, Peterson C, et al. Paricalcitol reduces albuminuria and inflammation in chronic kidney disease: a randomized doubleblind pilot trial. Hypertension 2008;52:249-55.  Back to cited text no. 11
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12.Scragg R, Sowers M, Bell C. Third National Health and Nutrition Examination Survey. Serum 25-hydroxyVitamin D, diabetes, and ethnicity in the Third National Health and Nutrition Examination Survey. Diabetes Care 2004;27:28132818.  Back to cited text no. 12
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13.Forman JP, Curhan GC, Taylor EN. Plasma 25-hydroxy Vitamin D levels and risk of incident hypertension among young women. Hypertension 2008; 52: 828-832.  Back to cited text no. 13
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14.McGill AT, Stewart JM, Lithander FE, Strik CM, Poppitt SD. Relationships of low serum Vitamin D3 with anthropometry and markers of the metabolic syndrome and diabetes in overweight and obesity. Nutr J 2008;7: 4  Back to cited text no. 14
    
15.Danesco LG, Levy S, Levy J. Vitamin D and diabetes mellitus. Endocrine 2009; 35: 11-17.  Back to cited text no. 15
    
16.Verrotti A, Basciani F, Carle F, Morgese G, Chiarelli F. Calcium metabolism in adolescents and young adults with type 1 diabetes mellitus without and with persistent microalbuminuria. J Endocrinol Invest 1999; 22(3):198-202.  Back to cited text no. 16
    
17.Nukai T, Fujiwara Y, Tayama K, Aso Y, Takemura Y. Alterations in serum levels of 1 alpha,25(OH)2 D3 and osteocalcin in patients with early diabetic nephropathy. Diabetes Res Clin Pract 1997; 38(1):53-9.  Back to cited text no. 17
    
18.Kano K, Nonoda A, Yoneshima H, Suda T. Serum concentrations of 25-hydroxyVitamin D and 24,25-dihydroxy Vitamin D in patients with various types of renal disease. Clin Nephrol 1980; 14(6):274-9.  Back to cited text no. 18
    
19.Pfeifer M, Begerow B, Minne HW, Nachtigall D, Hansen C. Effects of a short-term Vitamin D(3) and calcium supplementation on blood pressure and parathyroid hormone levels in elderly women. J Clin Endocrinol Metab 2001; 86(4):1633-7.  Back to cited text no. 19
    
20.Scragg R, Sowers M, Bell C. Serum 25-hydroxy Vitamin D, ethnicity, and blood pressure in the Third National Health and Nutrition Examination Survey. Am J Hypertens 2007; 20(7):713-9.  Back to cited text no. 20
    
21.Alonso A, Beunza JJ, Delgado-Rodriguez M, Martinez JA, Martinez-Gonzalez MA. Low-fat dairy consumption and reduced risk of hypertension: the Seguimiento Universidad de Navarra (SUN) cohort. Am J Clin Nutr 2005;82:972-9.  Back to cited text no. 21
    
22.Jauhiainen T, Korpela R. Milk peptides and blood pressure. J Nutr 2007;137(3 Suppl 2):825S-9S.  Back to cited text no. 22
    
23.Talmor Y, Bernheim J, Klein O, Green J, Rashid G. Calcitriol blunts pro‑atherosclerotic parameters through NFkappaB and p38 in vitro. Eur J Clin Invest 2008;38:548-54.  Back to cited text no. 23
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24.Pilz S, Tomaschitz A, Ritz E, Pieber T. Vitamin d status and arterial hypertension: A systematic review. Nat Rev Cardiol 2009;6: 621-30.  Back to cited text no. 24
    
25.Borissova AM, Tankova T, Kirilov G, Dakovska L, Kovacheva R. The effect of Vitamin D3 on insulin secretion and peripheral insulin sensitivity in type 2 diabetic patients. Int J Clin Pract 2003;57:258-61.  Back to cited text no. 25
    
26.Chiu KC, Chu A, Go VL, Saad MF. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr 2004;79:820-5.  Back to cited text no. 26
    
27.Heikkinen AM, Tuppurainen MT, Niskanen L, Komulainen M, Penttila I, Saarikoski S. Longterm Vitamin D3 supplementation may have adverse effects on serum lipids during post-menopausal hormone replacement therapy. Eur J Endocrinol 1997;137:495-502.  Back to cited text no. 27
    
28.Wehmeier K, Beers A, Haas MJ, et al. Inhibition of apolipoprotein AI gene expression by 1, 25-dihydroxyVitamin D3. Biochim Biophys Acta 2005;1737:16-26.  Back to cited text no. 28
    

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Correspondence Address:
Maryam Hami
Assistant Professor of Nephrology, Kidney Transplantation Complications Research Center, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad
Iran
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DOI: 10.4103/1319-2442.103562

PMID: 23168851

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