Skip to main content
Download PDF

The role of 25-hydroxyvitamin D deficiency in promoting insulin resistance and inflammation in patients with Chronic Kidney Disease: a randomised controlled trial

BMC Nephrology volume 10, Article number: 41 (2009) Cite this article

Abstract

Background

Approximately 50% of patients with stage 3 Chronic Kidney Disease are 25-hydroxyvitamin D insufficient, and this prevalence increases with falling glomerular filtration rate. Vitamin D is now recognised as having pleiotropic roles beyond bone and mineral homeostasis, with the vitamin D receptor and metabolising machinery identified in multiple tissues. Worryingly, recent observational data has highlighted an association between hypovitaminosis D and increased cardiovascular mortality, possibly mediated via vitamin D effects on insulin resistance and inflammation. The main hypothesis of this study is that oral Vitamin D supplementation will ameliorate insulin resistance in patients with Chronic Kidney Disease stage 3 when compared to placebo. Secondary hypotheses will test whether this is associated with decreased inflammation and bone/adipocyte-endocrine dysregulation.

Methods/Design

This study is a single-centre, double-blinded, randomised, placebo-controlled trial. Inclusion criteria include; estimated glomerular filtration rate 30-59 ml/min/1.73 m2; aged ≥18 on entry to study; and serum 25-hydroxyvitamin D levels <75 nmol/L. Patients will be randomised 1:1 to receive either oral cholecalciferol 2000IU/day or placebo for 6 months. The primary outcome will be an improvement in insulin sensitivity, measured by hyperinsulinaemic euglycaemic clamp. Secondary outcome measures will include serum parathyroid hormone, cytokines (Interleukin-1β, Interleukin-6, Tumour Necrosis Factor alpha), adiponectin (total and High Molecular Weight), osteocalcin (carboxylated and under-carboxylated), peripheral blood mononuclear cell Nuclear Factor Kappa-B p65 binding activity, brachial artery reactivity, aortic pulse wave velocity and waveform analysis, and indirect calorimetry. All outcome measures will be performed at baseline and end of study.

Discussion

To date, no randomised controlled trial has been performed in pre-dialysis CKD patients to study the correlation between vitamin D status with supplementation, insulin resistance and markers of adverse cardiovascular risk. We remain hopeful that cholecalciferol may be a safe intervention, with health benefits beyond those related to bone-mineral homeostasis.

Trial registration

Australian and New Zealand Clinical Trials Registry ACTRN12609000246280.

Peer Review reports

Background

Chronic Kidney Disease (CKD) is an independent predictor of all-cause and cardiovascular (CV) mortality[1]. Whilst it is true that traditional Framingham risk factors are amenable to intervention in CKD, the results of intervention may not be as efficacious as those obtained in the general population[2, 3]. Thus, it has been hypothesised that there is a unique milieu established in CKD, which causes excess CV burden by mechanisms that are as yet not fully understood.

Hypovitaminosis D, measured as circulating 25-hydroxyvitamin D (25-OHD), is now widely recognised as a spectrum state, incorporating both deficiency (25-OHD <37 nmol/L) and relative insufficiency (38-75 nmol/L)[4]. CKD is an independent risk factor for hypovitaminosis D3, the prevalence of which negatively correlates with falling estimated glomerular filtration rate (eGFR) from CKD stage 3 onwards[5]. To contextualise this, in a recent audit of our department, the prevalence of hypovitaminosis D3 was found to be 54% in patients with CKD stage 3, with 11% of individuals deficient and 43% insufficient (unpublished data).

Dobnig et al were amongst the first to demonstrate that patients in the general population with lower serum 25-OHD and 1,25-(OH)2D (the active metabolite) at baseline are at increased risk of all-cause and cardiovascular mortality[6]. Similar findings have been reported in the incident haemodialysis population, and in CKD stages 3 and 4[7, 8]. Furthermore, observational studies demonstrate that in End Stage Kidney Disease (ESKD), patients prescribed active vitamin D compounds appear to have a 26% reduction in mortality, independent of other cardiovascular risks, parathyroid hormone (PTH) and bone mineral markers[9].

There is now emerging mechanistic data from laboratory studies linking vitamin D to pathological processes that could explain cardiovascular risk modulation. These include insulin resistance, inflammation and bone-endocrine dysregulation.

Within the CKD population impaired glycaemic control is highly prevalent[5, 10], is associated primarily with an increase in target tissue insulin resistance[11], and is additive to the CV burden [12–14]. Insulin sensitivity in normoglycaemic adults has been shown to be improved with vitamin D supplementation[15], and several small studies involving haemodialysis patients have yielded similar results using 1,25-(OH)2D or it's analogues for 4-26 weeks [16–26]. Mechanisms that may explain this improvement include down-regulation of the Renin-Angiotensin-Aldosterone system (RAAS), and possibly up-regulation of the osteocalcin-adiponectin system.

RAAS over-activity is well characterised in vitamin D deficiency[27], although the underlying mechanism for this is not fully understood. Excessive RAAS activity leads to diminished activation of the intracellular insulin receptor substrate-1 (IRS-1) - phosphatidylinositol 3-kinase(PI3-K) signalling pathway. This ultimately decreases translocation of the GLUT-4 glucose transporters to the cell membrane in skeletal muscle; a process integral to augment the action of insulin and enhancing glucose uptake into cells[27, 28].

Osteocalcin is a bone protein secreted by osteoblasts, the transcription of which is known to be vitamin D responsive[29]. Additionally, osteoblasts express the vitamin D activating 1α-hydroxylase enzyme (CYP27B1) and ex vivo culture with the substrate 25-OHD yields greater mRNA production for osteocalcin than 1,25-(OH)2D, highlighting the possible importance of substrate availability[30]. Recent studies have linked osteocalcin to improved glycaemic handling in tissues[31], and osteocalcin knockout mice exhibit marked insulin resistance and an adverse metabolic phenotype[32]. High molecular weight (HMW) adiponectin is an adipokine that is known to improve glycaemic handling, and negatively correlates with insulin resistance[33]. Adiponectin release from adipocytes is stimulated by osteocalcin[32] and thus may be the linking intermediary.

Adverse glycaemic control is also associated with increased inflammatory stress[34, 35], as occurs in CKD, and the resultant pro-inflammatory state is associated with atherosclerosis[36, 37]. Vitamin D deficiency is associated with an increased inflammatory burden in humans[6], and this can be suppressed using 1,25-(OH)2D or its analogues, both in vitro and in vivo [38–41]. A major factor affecting cytokine production by circulating peripheral blood mononuclear cells (PBMCs) is Nuclear Factor Kappa-B (NfκB), a family of dimeric nuclear transcription factors that when activated are associated with the production of pro-inflammatory cytokines. Various groups have shown that the transcription factor NFκB family is linked to the vitamin D receptor (VDR) signalling pathway [42–44], and that vitamin D inhibits monocyte NFκB p65 activation with down stream suppression of various pro-inflammatory cytokines including Tumour Necrosis Factor alpha (TNFα), Interleukin (IL)-1β, and IL-6[45]. PBMCs also possess the CYP27B1 enzyme[45], which is up-regulated in uraemia but is not responsive to PTH and calcium like the renal isoform[46]. This raises the question whether, like osteoblasts, there may be more avid responses to supplementing the substrate precursor 25-OHD. Unfortunately, to date, Vitamin D intervention trials in the renal literature have predominantly used active 1,25-(OH)2D compounds and the results are discrepant, with groups reporting both decreased and no change in PBMC cytokine production, with no obvious correlation with serum cytokine profiles, in either a dose, duration or PBMC specific fashion[41, 47–54].

Whilst active vitamin D3 analogues have limited application due to side-effects (hypercalcaemia, hyperphosphataemia), vitamin D3 supplementation (as oral cholecalciferol) is well tolerated at both physiological and supra-physiological doses, is efficacious at raising 25-OHD levels, and is not associated with the same degree of mineral disturbance[55, 56].

This study aims to provide prospective data regarding the novel use of cholecalciferol, a safe and effective vitamin D supplement, to ameliorate insulin resistance in patients with CKD. Improvements in insulin sensitivity with cholecalciferol intervention will be assessed for association and possible causation with circulating inflammatory burden and bone/adipocyte-endocrine regulation. This will also be related to vascular function, a surrogate marker for cardiovascular risk.

Methods/Design

This trial is a double-blinded randomised controlled trial. Informed consent will be obtained from all participants. The study protocol has received approval from the Princess Alexandra Hospital Human Research Ethics Committee (PAH HREC), approval number 2009/097. The project is funded by a Princess Alexandra Hospital Private Practice Trust Fund Research Support Grant and a Neorecormon Research Grant from Roche Products Pty Limited.

Participants

All patients attending the Nephrology outpatient department at Princess Alexandra Hospital, Brisbane meeting inclusion criteria will be invited to participate. Inclusion criteria include: CKD stage 3 (eGFR[57] 30-59 ml/min/1.73 m2); age ≥18 or over; and serum 25-hydroxyvitamin D level <75 nmol/L. Exclusion criteria include: unable or unwilling to give informed consent; pre-menopausal status in females; death or dialysis expected within 6 months; recipient of a transplant; active (<1 month) inflammatory or infectious process or use of anti-inflammatory medication; corticosteroid use (<1 month); oral hypoglycaemic medication use; current or recent (<3 months) use of drugs affecting bone turnover, hepatic metabolism of vitamin D, steroids, or vitamin D containing compounds; malabsorptive state or lactose intolerant; active endocrine disorder (excluding diabetes); serum corrected calcium >2.54 mmol/L or phosphate >1.49 mmol/L.

Intervention

Randomised patients will receive either 2000IU oral cholecalciferol/day (two 25 μcg tablets, Ostevit-D, Key Pharmaceuticals Pty Limited, NSW) or two placebo tablets/day for a total duration of 6 months. Patients with serum calcidiol levels ≤37 nmol/L cannot be ethically randomised to placebo and will therefore be placed on cholecalciferol at a dose of 2000IU/day with subsequent follow up for 6 months. The non-randomised patients will be analysed primarily by dependent paired sampling, acting as their own control. If, in subsequent analysis, this group is found to have comparable baseline characteristics to the randomised groups, independent analysis will be performed.

Outcomes

All outcome measures will be performed at baseline and end of study. The primary outcome measure will be a change in the glucose disposal rate as a marker of insulin sensitivity as measured by the hyperinsulinaemic euglycaemic clamp[58]. Secondary outcome measures will include serum PTH, cytokines (IL-1β, IL-6, TNFα), adiponectin (total and High Molecular Weight), osteocalcin (carboxylated and under-carboxylated), and peripheral blood mononuclear cell NFκB p65 binding activity, all of which will be tested on -80°C stored serum (nuclear extract for NFκB) in batch by enzyme-linked immunosorbent assay (ELISA). Brachial artery reactivity, aortic pulse wave velocity and waveform analysis, and indirect calorimetry will also be assessed.

Sample size and randomisation

Prospective power calculations based on independent t testing indicate that the study will have adequate statistical power (80% probability) to detect a clinically significant increase in insulin sensitivity of 12%, assuming α = 0.05 and a population standard deviation of 10%, if 24 patients are recruited in the study (12 in each group). Using paired t testing for dependent sampling (non-randomised group, baseline to end of study), 8 patients will be needed. From previous experience within the renal unit of CKD trials, it is known that there is a high drop out rate because of progression to dialysis, death, intercurrent co-morbidity and loss to follow up. Allowing for a 20% drop out and using the adjustment factor 1/(1-v)2, a total of 51 patients will need to be recruited.

Randomisation will be by permuted block and stratified for baseline Body Mass Index (BMI, ≤25 Kg/m2 and >25 Kg/m2) and diabetic status. Randomisation will be performed off-site using a validated Microsoft Access Computer based system available through the Centre for Clinical Research Excellence Vascular and Metabolic Health at the University of Queensland. This will generate a unique treatment allocation number which will be ascribed to the patient blindly by the physician. Pharmacy will be un-blinded and dispense trial medication based upon the numeric reference prescription, using unmarked bottles, with generic administration details.

Statistical methods

Data will be assessed for normality of distribution and transformed as appropriate. The active intervention (Cholecalciferol) and placebo groups will be compared at baseline to determine the effectiveness of randomisation. Euglycaemic clamp data from a healthy, non-uraemic cohort will be supplied by IH and used for comparison. Any differences between the groups that may cause potential confounding (age, sex, ethnicity, BMI, lean:fat mass, eGFR, calcium, phosphate, PTH, inflammatory markers, proteinuria) will be assessed and adjusted for in the analysis by the use of appropriate multivariate techniques.

Statistical analyses will be performed using standard statistical software (Stata Version 10.0, Texas, USA). For parametric continuous data, results will be expressed as mean ± standard deviation, for non-parametric continuous data, results will be expressed as median (interquartile range, IQR), and for categorical data, results will be expressed as frequencies (percentages %). The degree of association between 25-hydroxyvitamin D and the variables of interest will be assessed using Pearson's correlation for continuous normally distributed variables and Spearman's correlation for categorical or non-parametric data. Linear or binary logistic regression will be performed as appropriate and standard regression diagnostics will be performed. Comparison of means for independent samples will be made using: unpaired t-test (parametric data); Mann-Whitney test (non-parametric data); and, Fisher's exact test or Pearson's Chi-square test (categorical data). Comparisons of means for dependent samples will be by paired samples t-test (parametric data); Wilcoxon signed rank test (non-parametric data); and, McNemar's test (categorical data).

No interim analysis is planned, but patients will be monitored for safety by biochemical testing (serum calcium and phosphate) at 3 months. Analysis of insulin resistance related to intervention will be by completed cases only. Secondary hypotheses will be assessed by analysis of available data and intention to treat.

The hypothesis will be accepted if the null hypothesis can be rejected at the 0.05 probability level.

Discussion

To date, no randomised controlled trial has been performed in pre-dialysis CKD patients to study the correlation between vitamin D status with supplementation, insulin resistance and markers of adverse cardiovascular risk. Given the limitations of active vitamin D compounds, we remain hopeful that cholecalciferol may be a safer intervention, with health benefits beyond those related to bone-mineral homeostasis. Ultimately, this trial will add much needed, controlled, prospective data to the field, and if positive, lead the way for a larger study focussed on addressing patient level outcomes in this challenging population.

References

  1. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu C: Chronic Kidney Disease and the Risks of Death, Cardiovascular Events, and Hospitalization. N Engl J Med. 2004, 351: 1296-1308. 10.1056/NEJMoa041031.

    CAS  Article  PubMed  Google Scholar 

  2. Rakhit DJ, Marwick TH, Armstrong KA, Johnson DW, Leano R, Isbel NM: Effect of aggressive risk factor modification on cardiac events and myocardial ischaemia in patients with chronic kidney disease. Heart. 2006, 92: 1402-1408. 10.1136/hrt.2005.074393.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Kaisar MO, Isbel NM, Johnson DW: Recent Clinical Trials of Pharmacologic Cardiovascular Interventions in Patients with Chronic Kidney Disease. Rev Recent Clin Trials. 2008, 3: 79-88. 10.2174/157488708784223853.

    CAS  Article  PubMed  Google Scholar 

  4. Holick MF: Sunlight and vitamin D for bone heath and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr. 2004, 80 (suppl): 1678S-1688S.

    CAS  PubMed  Google Scholar 

  5. Scragg R, Sowers M, Bell C: Serum 25-Hydroxyvitamin D, Diabetes, and Ethnicity in the Third National Health and Nutrition Examination Survey. Diabetes Care. 2004, 27: 2813-2818. 10.2337/diacare.27.12.2813.

    CAS  Article  PubMed  Google Scholar 

  6. Dobnig H, Pilz S, Scharnagl H, Renner W, Seelhorst U, Wellnitz B, Kinkeldei J, Boehm BO, Weihrauch G, Maerz W: Independent Association of Low Serum 25-Hydroxyvitamin D and 1,25 Dihydroxyvitamin D Levels With All-Cause and Cardiovascular Mortality. Arch Intern Med. 2008, 168: 1340-1349. 10.1001/archinte.168.12.1340.

    CAS  Article  PubMed  Google Scholar 

  7. Wolf M, Shah A, Gutierrez O, Ankers E, Monroy M, Tamez H, Steele D, Chang Y, Camargo CA, Tonelli M, Thadhani R: Vitamin D levels and early mortality among incident hemodialysis patients. Kidney International. 2007, 72: 1004-1013. 10.1038/sj.ki.5002451.

    CAS  Article  PubMed  Google Scholar 

  8. Inaguma D, Nagaya H, Hara K, Tatematsu K, Shinjo H, Suzuki S, Mishima T, Kurata K: Relationship between serum 1,25-dihydroxyvitamin D and mortality in patients with pre-dialysis chronic kidney disease. Clin Exp Nephrol. 2008, 12: 126-131. 10.1007/s10157-007-0023-4.

    CAS  Article  PubMed  Google Scholar 

  9. Wolf M, Thadhani R: Vitamin D in Patients with Kidney Disease: Cautiously Optimistic. Adv Chronic Kidney Dis. 2007, 14: 22-26. 10.1053/j.ackd.2006.10.009.

    Article  PubMed  Google Scholar 

  10. Chonchol M, Scragg R: 25-Hydroxyvitamin D, insulin resistance, and kidney function in the Third National Health and Nutrition Examination Survey. Kidney International. 2007, 71: 134-139. 10.1038/sj.ki.5002002.

    CAS  Article  PubMed  Google Scholar 

  11. DeFronzo RA, Alvestrand A, Smith D, Hendler R, Hendler E, Wahren J: Insulin Resistance in Uremia. J Clin Invest. 1981, 67: 563-568. 10.1172/JCI110067.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Armstrong KA, Campbell SB, Hawley CM, Nicol DL, Johnson DW, Isbel NM: Obesity is Associated with Worsening Cardiovascular Risk Factor Profiles and Proteinuria Progression in Renal Transplant Recipients. Am J Tranplant. 2005, 5: 2710-2718. 10.1111/j.1600-6143.2005.01073.x.

    Article  Google Scholar 

  13. Johnson DW, Armstrong KA, Campbell SB, Mudge DW, Hawley CM, Coombes JS, Prins JB, Isbel NM: Metabolic syndrome in severe chronic kidney disease: Prevalence, predictors, prognostic significance and effects of risk factor modification. Nephrology. 2007, 12: 391-398. 10.1111/j.1440-1797.2007.00804.x.

    CAS  Article  PubMed  Google Scholar 

  14. Levin A, Djurdjev O, Barrett B, Burgess E, Carlisle E, Ethier J, Jindal K, Mendelssohn D, Tobe S, Singer J, Thompson C: Cardiovascular disease in patients with chronic kidney disease: getting to the heart of the matter. Am J Kidney Dis. 2001, 38: 1398-1407. 10.1053/ajkd.2001.29275.

    CAS  Article  PubMed  Google Scholar 

  15. Pittas AG, Harris SS, Stark PC, Dawson-Hughes B: The Effects of Calcium and Vitamin D Supplementation on Blood Glucose and Markers of Inflammation in Nondiabetic Adults. Diabetes Care. 2007, 30: 980-986. 10.2337/dc06-1994.

    CAS  Article  PubMed  Google Scholar 

  16. Mak RHK: Amelioration of hypertension and insulin resistance by 1,25-dihydroxycholecalciferol in hemodialysis patients. Pediatr Nephrol. 1992, 6: 345-348. 10.1007/BF00869730.

    CAS  Article  PubMed  Google Scholar 

  17. Mak RHK: Intravenous 1,25 dihydroxycholecalciferol corrects glucose intolerance in hemodialysis patients. Kidney International. 1992, 41: 1049-1054. 10.1038/ki.1992.159.

    CAS  Article  PubMed  Google Scholar 

  18. Türk S, Yeksan M, Tamer N, Gürbilek M, Erdogan Y, Erkul Ï: Effect of 1,25 (OH)2 D3 treatment on glucose intolerance in uraemia. Nephrol Dial Transplant. 1992, 7: 1207-1212.

    PubMed  Google Scholar 

  19. Günal AÌ, Çelìker , Çelebì B, Üstündag , Günal SY: Intravenous alfacalcidol improves insulin resistance in hemodialysis patients. Clin Nephrol. 1997, 48: 109-113.

    PubMed  Google Scholar 

  20. Lin S, Lin Y, Lu K, Diang L, Chyr S, Liao W, Shieh S: Effects of intravenous calcitriol on lipid profiles and glucose tolerance in uraemic patients with secondary hyperparathyroidism. Clin Sci. 1994, 87: 533-538.

    CAS  Article  PubMed  Google Scholar 

  21. Quesada JM, Martín-Malo A, Santiago J, Hervas F, Martinez ME, Castillo D, Barrio V, Aljama P: Effect of Calcitriol on Insulin Secretion in Uraemia. Nephrol Dial Transplant. 1990, 5: 1013-1017.

    CAS  Article  PubMed  Google Scholar 

  22. Mak RHK: 1,25-Dihydroxyvitamin D3 corrects insulin and lipid abnormalities in uremia. Kidney International. 1998, 53: 1353-1357. 10.1046/j.1523-1755.1998.00865.x.

    CAS  Article  PubMed  Google Scholar 

  23. Allegra V, Luisetto G, Mengozzi G, Martimbianco L, Vasile A: Glucose-induced insulin secretion in uremia: role of 1 alpha,25(HO)2-vitamin D3. Nephron. 1994, 68: 41-47. 10.1159/000188085.

    CAS  Article  PubMed  Google Scholar 

  24. Strózecki P, Kretowicz M, Odrow-Sypniewska G, Manitius J: The Influence of Intravenous 1,25(OH)2D3 Therapy on Glucose Metabolism In Hemodialyzed Patients with Secondary Hyperparathyroidism. Renal Failure. 2004, 26: 345-348. 10.1081/JDI-120039815.

    Article  PubMed  Google Scholar 

  25. Blair D, Byham-Gray L, Lewis E, McCaffrey S: Prevalence of vitamin D [25(OH)D] deficiency and effects of supplementation with ergocalciferol (vitamin D2) in stage 5 chronic kidney disease patients. J Ren Nutr. 2008, 18: 375-82. 10.1053/j.jrn.2008.04.008.

    Article  PubMed  Google Scholar 

  26. Kautzky-Willer A, Pacini G, Barnas U, Ludvik B, Streli C, Graf H, Prager R: Intravenous calcitriol normalizes insulin sensitivity in uremic patients. Kidney International. 1995, 47: 200-206. 10.1038/ki.1995.24.

    CAS  Article  PubMed  Google Scholar 

  27. Rammos G, Tseke P, Ziakka S: Vitamin D, the renin-angiotensin system, and insulin resistance. Int Urol Nephrol. 2008, 40: 419-426. 10.1007/s11255-007-9244-4.

    CAS  Article  PubMed  Google Scholar 

  28. Sowers JR: Insulin resistance and hypertension. Am J Physiol Hear Circ Physiol. 2004, 286: H1597-H1602. 10.1152/ajpheart.00026.2004.

    CAS  Article  Google Scholar 

  29. Maruotti N, Corrado A, Grano M, Colucci S, Cantatore FP: Normal and osteoporotic human osteoblast behavior after 1,25-dihydroxyvitamin D3 stimulation. Rheumatol Int. 2009, 29: 667-672. 10.1007/s00296-008-0755-9.

    CAS  Article  PubMed  Google Scholar 

  30. Atkins GJ, Anderson PH, Findlay DM, Welldon KJ, Vincent C, Zannettino ACW, O'Loughlin PD, Morris HA: Metabolism of vitamin D3 in human osteoblasts: Evidence for autocrine and paracrine activities of 1a,25-dihydroxyvitamin D3. Bone. 2007, 40: 1517-1528. 10.1016/j.bone.2007.02.024.

    CAS  Article  PubMed  Google Scholar 

  31. Kanazawa I, Yamaguchi T, Yamamoto M, Yamauchi M, Kurioka S, Yano S, Sugimoto T: Serum osteocalcin level is associated with glucose metabolism and atherosclerosis parameters in type 2 diabetes mellitus. J Clin Endocrinol Metab. 2009, 94: 45-49. 10.1210/jc.2008-1455.

    CAS  Article  PubMed  Google Scholar 

  32. Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, Dacquin R, Mee PJ, McKee MD, Jung DY, Zhang Z, Kim JK, Mauvais-Jarvis F, Ducy P, Karsenty G: Endocrine Regulation of Energy Metabolism by the Skeleton. Cell. 2007, 130: 456-469. 10.1016/j.cell.2007.05.047.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. Hara K, Horikoshi M, Yamauchi T, Yago H, Miyazaki O, Ebinuma H, Imai Y, Nagai R, Kadowaki T: Measurement of the high-molecular weight form of adiponectin in plasma is useful for the prediction of insulin resistance and metabolic syndrome. Diabetes Care. 2006, 29: 1357-1362. 10.2337/dc05-1801.

    CAS  Article  PubMed  Google Scholar 

  34. Lee YH, Pratley RE: The evolving role of inflammation in obesity and the metabolic syndrome. Curr Diab Rep. 2005, 5: 70-75. 10.1007/s11892-005-0071-7.

    CAS  Article  PubMed  Google Scholar 

  35. Hak AE, Stehouwer CD, Bots ML, Polderman KH, Schalkwijk CG, Westendorp IC, Hofman A, Witteman JC: Associations of C-reactive protein with measures of obesity, insulin resistance, and subclinical atherosclerosis in healthy, middle-aged women. Arterioscler Thromb Vasc Biol. 1999, 19: 1986-1991.

    CAS  Article  PubMed  Google Scholar 

  36. Yilmaz MI, Carrero JJ, Axelsson J, Lindholm B, Stenvinkel P: Low-grade inflammation in chronic kidney disease patients before the start of renal replacement therapy: sources and consequences. Clin Nephrol. 2007, 68: 1-9.

    CAS  Article  PubMed  Google Scholar 

  37. Menon V, Wang X, Greene T, Beck GJ, Kusek JW, Marcovina SM, Levey AS, Sarnak MJ: Relationship between C-reactive protein, albumin, and cardiovascular disease in patients with chronic kidney disease. Am J Kidney Dis. 2003, 42: 44-52. 10.1016/S0272-6386(03)00407-4.

    CAS  Article  PubMed  Google Scholar 

  38. Andress D: Nonclassical Aspects of Differential Vitamin D Receptor Activation. Implications for Survival in Patients with Chronic Kidney Disease. Drugs. 2007, 67: 1999-2012. 10.2165/00003495-200767140-00003.

    CAS  Article  PubMed  Google Scholar 

  39. Schleithoff SS, Zitterman A, Tenderich G, Berthold HK, Stehle P, Koerfer R: Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr. 2006, 83: 754-759.

    CAS  PubMed  Google Scholar 

  40. Tan X, Wen X, Liu Y: Paricalcitriol Inhibits renal Inflammation by Promoting Vitamin D Receptor-Mediated Sequestration of NF-κB Signaling. J Am Soc Nephrol. 2008, 19: 1741-1752. 10.1681/ASN.2007060666.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Alborzi P, Patel NA, Peterson C, Bills JE, Bekele DG, Bunaye Z, Light RP, Agarwal R: Paricalcitol reduces Albuminuria and Inflammation in Chronic Kidney Disease. Hypertension. 2008, 52: 249-255. 10.1161/HYPERTENSIONAHA.108.113159.

    CAS  Article  PubMed  Google Scholar 

  42. Wang P, Anderson PO, Chen S, Paulsson KM, Sjögren HO, Li S: Inhibition of the transcription factors AP-1 and NF-kappaB in CD4 T cells by peroxisome proliferator-activated receptor gamma ligands. Int Immunopharmacol. 2001, 1: 803-812. 10.1016/S1567-5769(01)00015-7.

    CAS  Article  PubMed  Google Scholar 

  43. Lu X, Farmer P, Rubin J, Nanes MS: Integration of the NFκB p65 subunit into the vitamin D receptor transcriptional complex: identification of p65 domains that inhibit 1,25-dihydroxyvitamin D3-stimulatedtranscription. J Cell Biochem. 2004, 92: 833-848. 10.1002/jcb.20143.

    CAS  Article  PubMed  Google Scholar 

  44. Banwell CM, MacCartney DP, Guy M, Miles AE, Uskokovic MR, Mansi J, Stewart PM, O'Neill LP, Turner BM, Colston KW, Campbell MJ: Altered nuclear receptor corepressor expression attenuates vitamin D receptor signaling in breast cancer cells. Clinc Cancer Res. 2006, 12: 2004-2013. 10.1158/1078-0432.CCR-05-1218.

    CAS  Article  Google Scholar 

  45. Guijarro C, Egido J: Transcription factor-κB (NF-κB) and renal disease. Kidney International. 2001, 59: 415-424. 10.1046/j.1523-1755.2001.059002415.x.

    CAS  Article  PubMed  Google Scholar 

  46. Bell NH: Renal and Nonrenal 25-Hydroxyvitamin D-1[alpha]-Hydroxylases and Their Clinical Significance. J Bone Miner Res. 1998, 13: 350-353. 10.1359/jbmr.1998.13.3.350.

    CAS  Article  PubMed  Google Scholar 

  47. Borazan A, Üstün H, Cefle A, Sekitmez N, Yilmaz A: Comparative Efficacy of Oral and Intravenous Calcitriol Treatment in Haemodialysis Patients: Effects on Serum Biochemistry and Cytokine Levels. J Int Med Res. 2003, 31: 489-496.

    CAS  Article  PubMed  Google Scholar 

  48. Türk S, Akbulut M, Yildiz A, Gürbilek M, Gönen S, Tombul Z, Yeksan M: Comparative Effect of Oral Pulse and Intravenous calcitriol Treatment in Hemodialysis Patients: The Effect on Serum IL-1 and IL-6 Levels and Bone Mineral density. Nephron. 2002, 90: 188-194. 10.1159/000049041.

    Article  PubMed  Google Scholar 

  49. Panichi V, De Pietro S, Andreini B, Bianchi AM, Migliori M, Taccola D, Giovannini L, Tetta C, Palla R: Calcitriol modulates in vivo and in vitro cytokine production: A role for intracellular calcium. Kidney International. 1998, 54: 1463-1469. 10.1046/j.1523-1755.1998.00152.x.

    CAS  Article  PubMed  Google Scholar 

  50. Jaroszynski AJ, Ksiazek A: Changing relationships between serum IL-1, IL-6, and TNF-a and dynamic tests of parathyroid gland function in haemodialysis patients with severe hyperparathyroidism in response to calcitriol therapy. Nephrol Dial Transplant. 2000, 15: 1718-1719. 10.1093/ndt/15.10.1718.

    CAS  Article  PubMed  Google Scholar 

  51. Tsukamoto Y, Nagaba Y, Izumida I, Morishita T, Saitoh M: Comparison of effects of calcitriol and calcium carbonate on secretion of interleukin-1β and tumour necrosis factor-α by uraemic peripheral blood mononuclear cells. Nephrol Dial Transplant. 1996, 11 (Suppl 3): 15-21.

    CAS  Article  PubMed  Google Scholar 

  52. Riancho JA, Zarrabeitia MT, de Francisco ALM, Amado JA, Napal J, Arias M, Gonzalez-Macias J: Vitamin D Therapy Modulates Cytokine Secretion in Patients with Renal Failure. Nephron. 1993, 65: 364-368. 10.1159/000187514.

    CAS  Article  PubMed  Google Scholar 

  53. Yonemura K, Sugiura T, Yamashita F, Matsushima H, Hishida A: Supplementation with Alfacalcidol Increases Protein Intake and Serum Albumin Concentration in Patients Undergoing Hemodialysis with Hypoalbuminemia: Possible Role of Tumor Necrosis Factor-α. Blood Purification. 2004, 22: 210-215. 10.1159/000076855.

    CAS  Article  PubMed  Google Scholar 

  54. Moe SM, Zekonis M, Harezlak J, Ambrosius WT, Gassensmith CM, Murphy CL, Russell RR, Batiuk TD: Placebo-controlled trial to evaluate immunomodulatory effects of paricalcitol. Am J Kidney Dis. 2001, 38: 792-802. 10.1053/ajkd.2001.27697.

    CAS  Article  PubMed  Google Scholar 

  55. Chandra P, Binongo JN, Ziegler TR, Schlanger LE, Wang W, Someren JT, Tangpricha V: Cholecalciferol (vitamin D3) therapy and vitamin D insufficiency in patients with chronic kidney disease: a randomized controlled pilot study. Endocr Pract. 2008, 14: 10-17.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Tokmak F, Quack I, Schieren G, Sellin L, Rattensperger D, Holland-Letz T, Weiner SM, Rump LC: High-dose cholecalciferol to correct vitamin D deficiency in haemodialysis patients. Nephrol Dial Transplant. 2008, 12: 4016-4020. 10.1093/ndt/gfn367.

    Article  Google Scholar 

  57. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D: A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999, 130: 461-470.

    CAS  Article  PubMed  Google Scholar 

  58. DeFronzo RA, Tobin JD, Andres R: Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979, 237: E214-E223.

    CAS  PubMed  Google Scholar 

Pre-publication history

Download references

Acknowledgements

The authors would like to acknowledge the assistance of all the staff of the Nephrology outpatient department at Princess Alexandra Hospital for helping with recruitment, Dr Liza Phillips for assistance with the NFκB laboratory techniques, Diane Leary as study coordinator and to both the Princess Alexandra Hospital Foundation Trust and Roche for their financial support. WP also gratefully acknowledges both the CCRE and Department of Nephrology at the University of Queensland for their scholarship and resource support.

Author information

Authors and Affiliations

  1. Department of Nephrology, University of Queensland at Princess Alexandra Hospital, Brisbane, Australia

    William G Petchey, Carmel M Hawley, David W Johnson, Katherine Barraclough & Nicole M Isbel

  2. Diamantina Institute for Cancer, Immunology and Metabolic Medicine, University of Queensland, Brisbane, Australia

    Ingrid J Hickman, Emma Duncan & Johannes B Prins

  3. Centres of Health Research, Princess Alexandra Hospital, Brisbane, Australia

    Johannes B Prins

Authors
  1. William G Petchey
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ingrid J Hickman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Emma Duncan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Johannes B Prins
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Carmel M Hawley
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David W Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Katherine Barraclough
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nicole M Isbel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to William G Petchey.

Additional information

Competing interests

This study has received funding from a Neorecormon Research Grant (Roche Products) and a Private Practice Trust Fund Research Support Grant (Princess Alexandra Research Foundation).

Authors' contributions

WP conceived the study, wrote the protocol and ethics submission, secured the Roche NRG award and is co-principal investigator on the trial. IH assisted with protocol design and assisted with performing hyperinsulinaemic euglycaemic clamps on participants. JP and EH assisted in the trial design, specifically the components pertaining to end-organ insulin resistance, vitamin D physiology and bone-energy metabolism respectively. CH and DJ advised on the statistical analysis, study design and helped with recruitment of patients. KB recruited patients and gave technical assistance in preparation of the manuscript. NI supervised and assisted with protocol and trial design, secured PAH Foundation Trust funding, and is co-principal investigator for the trial. All authors read and approved the final manuscript.

Rights and permissions

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and Permissions

About this article

Cite this article

Petchey, W.G., Hickman, I.J., Duncan, E. et al. The role of 25-hydroxyvitamin D deficiency in promoting insulin resistance and inflammation in patients with Chronic Kidney Disease: a randomised controlled trial. BMC Nephrol 10, 41 (2009). https://doi.org/10.1186/1471-2369-10-41

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/1471-2369-10-41

Keywords

  • Chronic Kidney Disease
  • Chronic Kidney Disease Stage
  • Aortic Pulse Wave Velocity
  • Ameliorate Insulin Resistance
  • Princess Alexandra Hospital

BMC Nephrology

ISSN: 1471-2369

Contact us