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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Kidney Int. Author manuscript; available in PMC Nov 1, 2009.
Published in final edited form as:
PMCID: PMC2737358
NIHMSID: NIHMS108005

Reduction of the vitamin D hormonal system in kidney disease is associated with increased renal inflammation

Abstract

To examine any potential role for 1,25-dihydroxyvitamin D (1,25(OH)2D) in inflammation associated with chronic kidney disease we measured vitamin D metabolites, markers of inflammation and gene expression in 174 patients with a variety of kidney diseases. Urinary MCP-1 protein and renal macrophage infiltration were each significantly but inversely correlated with serum 1,25(OH)2D levels. Logistic regression analysis with urinary MCP-1 as binary outcome showed that a 10-unit increase in serum 1,25(OH)2D or 25OHD resulted in lower renal inflammation. Analysis of 111 renal biopsies found that renal injury was not associated with a compensatory increase in mRNA for the vitamin D-activating enzyme 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1), its catabolic counterpart 24-hydroxylase, or the vitamin D receptor. There was, however, a significant association between tissue MCP-1 and CYP27B1. Patients with acute renal inflammation had a significant increase in urinary and tissue MCP-1, macrophage infiltration, and macrophage and renal epithelial CYP27B1 expression but significantly lower levels of serum 1,25(OH)2D in comparison to patients with chronic ischemic disease despite similar levels of renal damage. In vitro, 1,25(OH)2D attenuated TNFα-induced MCP-1 expression by human proximal tubule cells. Our study indicates that renal inflammation is associated with decreased serum vitamin D metabolites and involves activation of the paracrine/autocrine vitamin D system.

Keywords: VDR, inflammation, vitamin D, CYP27B1, CYP24A1, chronic kidney disease

The importance of vitamin D to renal physiology has been recognized for many years. Synthesis of the active, hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D), from its inactive precursor (25-hydroxyvitamin D, 25OHD) occurs primarily in the proximal tubules of the kidney1,2 and supports the key endocrine actions of vitamin D.3 Recently, it has become clear that 1,25(OH)2D has potent immunomodulatory and antiproliferative properties, suggesting a role for vitamin D in the pathophysiology of autoimmune disease,4 common cancers,5 hypertension,6,7 renal inflammation,810 and cardiovascular disease.6,1113 Most of these nonclassical actions have been attributed to autocrine synthesis of 1,25(OH)2D, without changes in serum 1,25(OH)2D levels. Nevertheless, the kidney remains an integral component of normal vitamin D metabolism and function, with the vitamin D-activating enzyme 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1), its catabolic counterpart 24-hydroxylase (CYP24A1), and the nuclear vitamin D receptor (VDR), involving in determining the circulating levels of 1,25(OH)2D.1,14

In chronic kidney disease (CKD), perturbation of the vitamin D hormonal system is associated with progressive loss of renal function and may lead to skeletal,15 cardiovascular, 12,13 and renal9 complications, contributing directly to premature death.12,13 Although serum 1,25(OH)2D levels decline early in CKD,16,17 mainly as a consequence of decreased renal synthesis of the hormone, the predominant defect that underlies this remains unclear. Abnormal CYP27B1 activity may be due to: decreased kidney mass,14,1618 inhibition of CYP27B1 expression,19,20 dysregulated CYP27B1 expression,21 or decreased availability of substrate for CYP27B1.17 Circulating levels of 1,25(OH)2D may also reflect aberrant activity of CYP24A1, which is abundantly expressed in the kidney and catalyses conversion of 1,25(OH)2D to inactive metabolites.22,23 Another facet of vitamin D that may impact significantly on CKD concerns is its potent antiproliferative and immunomodulatory actions. For example, 1,25(OH)2D has been shown to modulate renal inflammation and fibrosis.810,24 These processes have been primarily attributed to the paracrine/autocrine effects of vitamin D.10,25,26 However, other studies using vitamin D analogs have indicated that the endocrine vitamin D system may also contribute to immunomodulatory responses.8,9,24

Macrophage chemoattractant protein-1 (MCP-1) is expressed in injury and inflammation to direct macrophage recruitment.27,28 1,25(OH)2D has been shown to be able to inhibit this MCP-1 driven inflammatory process by blocking nuclear factor-κB activation, potentially protecting the kidney.29

In this work, we have used a cohort of kidney disease patients to show for the first time a link between vitamin D metabolism and renal inflammation.

RESULTS

Markers of renal impairment in a kidney disease population undergoing renal biopsy

A total of 174 kidney disease patients (99 men, 75 women; 81.6% white, 10.9% Asian, 6.9% Afro-Caribbean) were studied. Of these, 111 had frozen kidney biopsy tissue available for PCR analysis. Data in Table 1 show clinical parameters and Table 2 shows pathological diagnoses, creatinine clearance (CrCl), and index of chronic damage. The degree of renal impairment depended on disease subclassification, with thin glomerular basement membrane disease (TBMD) patients (CrCl: 103.4±34.2 ml/min; index of chronic damage 2.2±3.5%) showing relatively intact renal parenchyma (Table 2, Figure 3a and b) when compared with renal vasculitis (25.9±39.4 ml/min; index of chronic damage 46.7±34.4%) or interstitial nephritis patients (CrCl: 11.3±12.0 ml/min; index of chronic damage 70.3±40.4%). Bivariate analyses showed that CrCl correlated negatively with the index of chronic renal damage (r=0.665, P<0.001), macrophage infiltration (r=0.583, P<0.001), and urinary MCP-1 concentration (r=0.372, P<0.001) (data not shown).

Figure 3
Analysis of renal biopsy patients according to disease diagnostic groups
Table 1
Study population, n=174: clinical and pathological characteristics
Table 2
Study population: pathological diagnosis on the renal biopsy, creatinine clearance, and index of chronic renal damage

Renal impairment, renal inflammation, and the vitamin D hormonal system

To relate the different markers of renal impairment outlined in Table 1 and Table 2, with serum and RNA measures of vitamin D metabolism and function, we used several different methods of comparison. With multiple linear regression analysis, a negative correlation was observed between serum 1,25(OH)2D and renal scarring (β=−0.430, P<0.001) and urinary MCP-1 levels (β=−0.179, P=0.026). By contrast, no correlation was observed between serum 1,25(OH)2D and serum intact parathyroid hormone, a known regulator of the renal vitamin D endocrine system. Serum 1,25(OH)2D also correlated with serum 25OHD (β=0.272, P=0.001) (Table 3a), and, as expected, renal CYP27B1 mRNA correlated positively with serum 1,25(OH)2D (β=−0.272, P=0.012), and showed no correlation with serum intact parathyroid hormone (Table 3b). Although serum 1,25(OH)2D levels correlated with renal impairment (Table 3a), no similar association was observed for CYP27B1 mRNA and chronic renal scarring (Table 3b) or CrCl (data not shown). CYP27B1 mRNA expression was negatively correlated with 24-h urinary protein excretion (β=0.349, P=0.013), whereas MCP-1 mRNA expression correlated positively with CYP27B1 mRNA (β=0.529, P=0.002). To investigate further, the effect of CKD on the expression of genes associated with vitamin D metabolism and function, linear regression analyses were carried out for CYP27B1, CYP24A1, and VDR mRNAs. Data indicated that loss of renal mass, declining serum 1,25(OH)2D levels, and deteriorating renal function, as defined by CrCl and increasing chronic renal damage, was not associated with altered expression of mRNAs for CYP27B1, CYP24A1, or VDR (Figure 1).

Figure 1
Effects of CKD on the expression of vitamin D-associated genes in renal biopsy tissue
Table 3
Correlates of serum 1,25(OH)2D and renal CYP27B1 mRNA expression in renal biopsy patients

Linear regression was also used to characterize further the relationship between renal impairment and inflammation with serum concentrations of 25OHD and 1,25(OH)2D (Figure 2). The latter confirmed linear regression data in Table 3a by showing a negative correlation with urinary MCP-1 (r=0.342, P<0.001), macrophage infiltration (r=0.537, P<0.001), renal scarring (r=0.546, P<0.001) (Figure 2a), and renal MCP-1 mRNA (r=0.342, P=0.003) (data not shown). Serum 25OHD showed similar correlation trends to 1,25(OH)2D but this was only statistically significant for renal scarring (r=0.343, P<0.001) (Figure 2b) and renal MCP-1 mRNA (r=0.260, P=0.024) (data not shown). As an alternative model for correlation between renal inflammation and serum vitamin D, logistic regression was used, with urinary MCP-1 as a binary outcome variable (Table 4). Previous studies from our group reported a mean urinary MCP-1 of 245±243 pg/mg creatinine in a similar CKD patient population with chronic inflammation.27 Therefore, to assess the potential role of vitamin D in a more acute inflammatory environment, a ‘cut-off ’ value of 300 pg/mg creatinine for urinary MCP-1 was selected. Comparing urinary MCP-1 ≤300 with >300 mg/mg creatinine, a 10 unit increase in serum 1,25(OH)2D reduced the odds ratio (OR) to 0.75 (95% CI 0.65–0.88) for patients being in the group with higher urinary MCP-1, after adjusting for age, gender, ethnicity, and index of chronic renal damage (Table 4). The same observation was made for serum 25OHD (OR 0.71; 95% CI 0.57–0. 90).

Figure 2
Relationship between serum vitamin D metabolites and markers of renal inflammation and CKD
Table 4
Logistic regression model for urinary MCP-1

Dysregulation of the vitamin D hormonal system with different forms of kidney disease

To provide an additional perspective on the vitamin D hormonal system in CKD, data were also analyzed on the basis of patient pathological/diagnostic groupings. The TBMD group was selected as a control population with minimal impaired renal function, scarring, and renal inflammation. Patients with renal vasculitis or interstitial nephritis were referred to as the acute inflammation group (inflammation) and compared with the other three groups. Patients in the acute inflammation had similar chronic renal damage to the ischemia group (28 vs 32% of area, P=NS) (Figure 3b), but much lower levels of CrCl (7 vs 40 ml/min, P=0.001) (Figure 3a), higher macrophage infiltration (6.6 vs 1.8% of area, P<0.001) (Figure 3c), and higher urinary MCP-1 (976.8 vs 143.9 pg/mg creatinine, P<0.001) (Figure 3d), reflecting the more acute, inflammatory nature of CKD in these patients. Consistent with this, serum 1,25(OH)2D levels were much lower in the inflammation group compared with the ischemia patients (29.6 vs 67.1 pmol/l, P=0.008) (Figure 3e). However, there was no significant difference in serum 25OHD levels between the groups studied (Figure 3f). Analysis of biopsy tissue mRNA expression showed that levels of renal CYP27B1 and at the same time probably also of CYP24A1 and VDR were increased in acute renal inflammation (Figure 4).

Figure 4
Analysis of renal biopsy patients according to disease diagnostic groups

In human kidney biopsies from patients with interstitial nephritis, CYP27B1 protein expression was localized to areas with immune cell infiltrate. Staining of consecutive sections confirmed CYP27B1 protein to be colocalized to macrophages (CD68+VE cells) (Figure 5c–f). Strong CYP27B1 protein staining was also found in renal tubular cells near to immune cell infiltration (Figure 5c,e). Normal kidney expressed CYP27B1 protein along the tubules with almost no immune cells in the renal interstitium (Figure 5a and b).

Figure 5
Localization of CYP27B1 protein and macrophages by immunohistochemistry in paraffin sections from human kidney biopsies

Regulation of MCP-1 expression by vitamin D in vitro

To investigate further a link between the vitamin D hormonal system and renal inflammation, additional studies were carried out in vitro. Results in Figure 6 showed that inflammatory activation of proximal tubular epithelial cells with tumor necrosis factor-α stimulated MCP-1 production by these cells, and this was attenuated following coincubation with 1,25(OH)2D (P=0.045), suggesting a possible role for vitamin D as a modulator of renal inflammation.

Figure 6
1,25(OH)2D suppresses expression of MCP-1 synthesis in primary cultures of human proximal renal tubular epithelial cells

DISCUSSION

Consistent with previously published studies, we confirmed that increased renal impairment is associated with decreased circulating levels of 1,25(OH)2D,1618 although this was not associated with significant changes in CYP27B1 mRNA expression. To the best of our knowledge, this is the first study to describe the expression of vitamin D-related genes in material from patients undergoing a diagnostic kidney biopsy. As such, the only other available CKD model for comparison is a rat model that has utilized three-fourth nephrectomy, respectively, to mimic CKD.30 In these rats, the renal impairment caused by substantial loss of renal mass was associated with a compensatory increase in mRNA for CYP27B1, and decreased expression of CYP24A1 and VDR mRNA in the kidney remnant, with resulting normalized serum 1,25(OH)2D levels. Clearly, it is difficult to draw a direct comparison between the rat model and our data. However, indirect measurement of renal endocrine function in humans, with falling serum 1,25(OH)2D levels already as a consequence of mild CKD seems to support our observations.1618 One possible explanation for the lack of change in CYP27B1 expression with renal impairment is that the predominant determinant of decreased serum 1,25(OH)2D in CKD patients is indeed loss of functional renal mass. Alternatively, CKD may be associated with altered expression of CYP27B1 and CYP24A1 mRNA splice variants that are not readily detected by standard real-time RT–PCR but are still able to modulate 25OHD metabolism.21,31 A further explanation is that the analysis of mRNA for CYP27B1 mRNA does not adequately reflect changes in the protein for this enzyme. Previous studies have shown that, during normal physiology, there is a strong correlation between expression of mRNA for CYP27B1 and capacity to synthesize 1,25(OH)2D.32,33 However, more recent analysis of the suppression of 1,25(OH)2D production in hypophosphatemic hyp mice concluded that control of CYP27B1 activity in these animals occurred at a post-transcriptional level.34 Owing to the constraints of tissue availability, we were unable to evaluate CYP27B1 protein expression or enzyme activity in renal biopsies. It is therefore possible that the decreased capacity for synthesis of 1,25(OH)2D associated with CKD also involves a decline in protein rather than mRNA for CYP27B1.

Data from this study indicate that another crucial determinant of endocrine and autocrine 1,25(OH)2D in CKD is serum 25OHD. Linear regression showed a strong correlation between the active form of vitamin D and its precursor, which contrasts the lack of direct correlation between serum 25OHD and 1,25(OH)2D concentrations previously reported in normal subjects.35 From this observation and the apparent retention of CYP27B1 expression in situ, we can hypothesize that CKD patients with 25OHD sufficiency will maintain adequate 1,25(OH)2D production. A central question concerning the low levels of circulating 25OHD concentrations in CKD is whether this actively contributes to renal inflammation with progression of renal disease. To address the contribution of circulating 25OHD concentration, renal inflammation and progression of renal disease issue further, analysis of serum vitamin D metabolites was carried out according to CKD disease type. Although there was a trend toward lower levels of 25OHD in more severe forms of CKD, we did not find a statistically significant variation with disease severity. Nevertheless, these data provide support for future studies to assess the impact of vitamin D supplementation on changes in renal impairment associated with CKD.

In CKD, a progressive decline in renal function is associated with worsening tubulointerstitial and glomerular scarring.36 Data presented here show a close association between kidney function and the histological quantification of tubulointerstitial fibrosis. Renal scarring is associated with an immune cell infiltrate consisting primarily of macrophages,37 which increases with deteriorating renal function27 in response to local synthesis of the inflammatory chemokine MCP-1, with accelerated tissue inflammation and injury.27,37,38 This is illustrated by the high levels of macrophage infiltration and MCP-1 in acute renal inflammation, which parallels the significant decline in renal impairment seen in these patients. In the light of accumulating evidence for the importance of the vitamin D hormonal system for the modulation of local inflammation, in particular renal inflammation,810,24,29 several of our observations are important, notably the logistic regression analyses (Table 4). Although these data suggest that enhancement of the vitamin D endocrine system is anti-inflammatory, it is also possible that the effect of 25OHD is being mediated at a local, autocrine/paracrine level. Specifically, characterization of the acute inflammation disease group revealed increased expression of CYP27B1 mRNA and protein despite decreased circulating levels of 1,25(OH)2D. Analysis of interstitial infiltration by immune cells and immune staining of consecutive tissue sections for macrophages and CYP27B1 protein suggests that activated macrophages are the likely source of this enhanced CYP27B1 expression,39 although renal epithelial cells26 and endothelial cells40 may also contribute to localized synthesis of 1,25(OH)2D following inflammation. The observed positive trend between CYP27B1 and CYP24 mRNA in acute inflammation also suggest a role for autocrine synthesis of 1,25(OH)2D, as described for bone25 and is in contrast to its known regulation in renal tubular cells.25,26 Indeed, the addition of exogenous 1,25(OH)2D was able to suppress TNF-α-induced MCP-1 expression by renal epithelial cells in vitro, an effect likely caused by 1,25(OH)2D targeting of nuclear factor-κB.29 Renal conversion of 25OHD to 1,25(OH)2D may provide an, as yet unrecognized, anti-inflammatory function for renal CYP27B1 activity.

MATERIALS AND METHODS

Patient recruitment and tissue collection

Following local ethical committee approval (RRK2608), patients underwent renal biopsy in the department of nephrology at the Queen Elizabeth Hospital (Birmingham, UK), for investigation of proteinuria and/or hematuria and/or renal impairment. Patients taking vitamin D metabolites were excluded. Renal biopsy material was divided and one part was snap frozen. The other part was fixed in formalin–saline and glutaraldehyde for routine pathological study. Relevant clinical data are shown in Table 1 and the main pathological diagnoses are shown in Table 2.

Laboratory analysis

Serum and urinary creatinine was measured using the method of Jaffe41 and CrCl calculated from a 24-h urine collection, performed before renal biopsy. Urinary MCP-1 was quantified using a commercially available sandwich ELISA kit (R&D Systems, Minneapolis, MN, USA), and levels corrected for urinary creatinine. Serum 25OHD (intraassay variation 5–6%, interassay variation 7–8%) (specificity for 25OHD2 75% and 25OHD3 100%) and 1,25(OH)2D (intraassay variation 5–8%, interassay variation 9–10%) (specificity for 1,25(OH)2D2 91% and 1,25(OH)2D3 100%) were measured using an IDS Gamma-B radioimmunoassay (IDS, Boldon, UK). Intact parathyroid hormone was measured using an immunoradiometric method, the Nichols intact parathyroid hormone assay (Nichols Institute Diagnostics, San Clemente, CA, USA).

Quantitative (real-time) RT-PCR analysis of CYP27B1, CYP24A1 VDR, and MCP-1 mRNA in renal biopsies

Total RNA was isolated from frozen kidney biopsies using the GenElute RNA extraction system (Sigma, Poole, UK). Aliquots (1.5 µg) of RNA from each biopsy were then reverse transcribed using AMV reverse transcriptase (Promega, Southampton, UK). Gene-specific PCR was then carried out using an ABI 7700 sequence detection system (PE Biosystems, Warring, UK) as described previously,42 using primers and probes outlined below under the following conditions: 50 °C for 2 min; 95 °C for 10 min; followed by 44 cycles of 95 °C for 15 s and 60 °C for 1 min.

Primers and probes for PCR reactions

Primer and probe sequences for CYP27B1, VDR, and CYP24A1 were as follows: CYP27B1, forward primer 5′-TTGGCAAGCGCAGCTGTAT-3′, reverse primer 5′-TGTGTTAGGATCTGGGCCAAA-3′, Taq-Man probe 5′-TTGCAATTCAAGCTCTGCCAGGCG-3′; VDR, forward primer 5′-CTTCAGGCGAAGCATGAAGC-3′, reverse primer 5′-CCTTCATCATGCCGATGTCC-3′, TaqMan probe 5′-AAGGCACTATTCACCTGCCCCTTCAA-3′; CYP24A1, forward primer 5′-CAAACCGTGGAAGGCCTATC-3′, reverse primer 5′-AGTCTTCCCCTTCCAGGATCA-3′, TaqMan probe 5′-ACTACCGCAAAGAAGGCTACGGGCTG-3′. The primers and probe for MCP-1 were commercially available assays on demand (Applied Biosystems, UK).

Measurement of chronic kidney damage

An interactive image analysis system was used to outline and measure the extent of glomerular and interstitial scarring, expressed as percentage of cortical cross-sectional area, in biopsies stained with periodic acid–methenamine silver. This measure, the index of chronic damage, is a strong predictor of renal outcome.36

Analysis of macrophage infiltration and CYP27B1 expression of renal tissue

Immunohistochemical detection of tissue macrophages and interactive image analysis was performed as previously described.27 Coded sections stained for CD68 were visualized at ×200 magnification and the image captured digitally by an Aequitas image database and image archive management system (Dynamic Data Links, Cambridge, UK). Each image was then converted to a two-color scale image by Aequitas image analysis software. By altering the threshold, the image was processed so that positive staining was represented by black pixels and measured as a percentage of the area of total image analyzed. For each patient, the mean measurement of five randomly selected nonconfluent microscopic fields of renal cortex was determined. Glomerular staining was excluded from the analysis by the computer software. Sections where background staining made it impossible to digitally differentiate specific staining were excluded from analysis. Immunohistochemical analysis of CYP27B1 protein on paraffine embedded human kidney biopsies was performed using previously described methods.43

Primary culture of human proximal tubular epithelial cells

Human proximal tubular epithelial cells were grown using described methodologies.44 Cells were used up to three passages for experimental treatments (24 h) included TNF-α (1 ng/ml), 1,25(OH)2D (10−7 m) alone and TNF-α (1 ng/ml) with 1,25(OH)2D (10−7 m). Epithelial MCP-1 production was quantified with the commercially available sandwich ELISA kit according to manufacturer’s (R&D Systems) instructions and levels corrected for total cellular protein.

Statistical analysis

Data were expressed as mean ± s.d. unless otherwise (threshold cycle for amplification of the target gene (CT) minus CT for 18S rRNA) stated. Statistical analysis on real-time PCR was performed on dCT values. Importantly, the quantification of mRNA from the gene of interest provides a larger difference to the house-keeping gene, when fewer target mRNA can be found in tissue. This can lead to the description of a negative association, where a positive association is described and vice versa. Comparison between groups was undertaken with paired and unpaired t-tests, analysis of variance, or the Mann–Whitney rank-sum test where appropriate. Linear regression analyses were performed to determine relationship between data variables, with appropriate transformations of items with non-normal distributions. Stepwise multivariable linear regression analysis was performed to identify statistically significant predictors. Final models were assessed for colinearity and regression diagnostics checked to ensure models were reasonable fit to data. Relationships are presented as standardized β-coefficient with the P-value. Analyses were performed using SPSS for Windows, version 12.0, and the level of significance was set at P<0.05.

Multiple logistic regression models allowed for adjustment of OR for potential confounding effects of age, gender, ethnicity, and index of chronic renal scarring. Logistic models were fitted using the SAS statistical package and their appropriateness assessed using Hosmer–Lemeshow goodness-of-fit tests and colinearity diagnostics.

ACKNOWLEDGMENTS

We thank Guerman Molostvov and Sean James for their help with immunohistochemistry.

Source of support: This work (MH) was supported by a grant from the Foundation for Nephrology and NIH grant R01AI076292.

Footnotes

Part of these studies were presented at the 37th annual meeting of the American Society of Nephrology, 27 October to 1 November 2004; St Louis, Missouri, USA.

DISCLOSURE

All the authors declared no competing interests.

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