Urinary soluble CD163: a non-invasive biomarker to monitor lupus nephritis

doi:10.21203/rs.3.rs-1765887/v1

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Urinary soluble CD163: a non-invasive biomarker to monitor lupus nephritis

https://doi.org/10.21203/rs.3.rs-1765887/v1

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Due to the role of macrophages in glomerular inflammation, macrophage surface molecules such as CD163 and CD11b represent attractive biomarkers for monitoring Lupus Nephritis (LN). We hypothesize that their urinary levels may reflect kidney disease activity. Here, we first analyzed the levels of urinary soluble CD163 (U-sCD163) and CD11b (U-sCD11b) in a cohort of 40 patients with LN including 23 with active disease. U-sCD163 levels were significantly elevated in active LN and correlated with the renal activity score, in contrast to U-sCD11b. Then, we developed the pristane induced LN mouse model to analyze, in a longitudinal way, the evolution of U-sCD163 levels according to the glomerular inflammation progression and response to treatment. We showed an increase of U-sCD163 levels associated with glomerular immune-complex deposits on mouse kidney biopsies at an early stage of the disease and a correlation with inflammatory markers including interferon-α, C-reactive protein and tumor necrosis factor-α. In addition, we showed that U-sCD163 levels decreased following efficient hydroxychloroquine treatment. Altogether our results led us to conclude that U-sCD163 represent a non-invasive biomarker for LN reflecting glomerular inflammation. Although prospective study in patients with LN, active or not, are necessary, U-sCD163 could be proposed to monitor response to treatment.

Lupus nephritis

urine biomarker

sCD163

sCD11b

disease monitoring

hydroxychloroquine

response to treatment

mouse model

Lupus nephritis (LN) is the major cause of morbidity and mortality in patients with Systemic Lupus Erythematosus (SLE)¹. According to the International Society of Nephrology/Renal Pathology Society (ISN/RPS), LN is stratified into different classes based on histological analysis². Classes III and IV ± V LN with active lesions are called “active LN” and represent the most severe forms of LN that can lead to end-stage kidney disease. In addition to the baseline treatment of SLE with hydroxychloroquine (HCQ), aggressive immunosuppressive therapies presenting possible side effects are required in active LN ^3,4. Early recognition of kidney damage in SLE patients represents an important challenge for clinical and therapeutic management. Kidney biopsy (KB) is the « gold standard » for the diagnosis and classification of LN but it remains an invasive procedure with a risk of bleeding complications and cannot be performed repeatedly to assess response to treatment⁵. In addition, a sampling bias is possible, and KB may not reflect accurately kidney inflammation. Therefore, non-invasive methods are clinically advisable for both initial diagnosis and monitoring of LN activity. Existing biomarkers, such as anti-native DNA antibodies, serum complement C3 and C4, serum creatinine, proteinuria or urinary sediment are already routinely used to monitor and evaluate SLE disease activity and LN⁶. However, these biomarkers lack sensitivity and specificity, especially to differentiate active lesions from chronic damage, and to assess histological remission. Others non-invasive markers should be investigated to predict and monitor LN injury in a more specific manner, and to help the therapeutic decision with maintaining, reducing, or weaning immunosuppressive therapies.

Development and progression of LN are associated with immunological mechanisms in which macrophages are involved in glomerular inflammation ^7,8. Surface markers expressed by macrophages, such as CD11b and CD163, have been found associated with LN activity and poor renal prognosis ⁹. CD11b is the α-subunit of leukocyte integrin Mac-1 expressed by neutrophils and monocytes/macrophages ¹⁰. CD163 is a scavenger receptor for the hemoglobin-haptoglobin complex expressed by monocytes and M2 polarized macrophages^11,12. Upon macrophage activation, CD163 and CD11b are shed from the cell surface into circulation. Thus, the soluble form of CD163 (sCD163) and CD11b (sCD11b) have raised scientific interest as possible markers in LN. Interestingly, some recent studies have reported that urinary levels of sCD11b (U-sCD11b) and sCD163 (U-sCD163) could reflect LN glomerular damage in LN patients ^13,14.

All these data led us to hypothesis that levels of U-sCD163 and U-sCD11b could reflect kidney disease activity because of their association with the progression of the glomerular inflammation.

In this line, we first analyzed the levels of U-sCD163 and U-sCD11b in a cohort of SLE patients sampled at the time of kidney biopsy. Then, we developed a pristane-induced mouse model of LN in order to longitudinally analyze urinary levels of biomarkers as a function of the progression of the glomerular inflammation and the response to treatment.

Clinical and biological characteristics of SLE patients

A total of 40 SLE patients (4 men and 36 women) were included in this study with 23 patients with active LN, and 17 patients with inactive LN. Clinical and biological data were compared between these two groups as reported in Table 1.

Table 1

**Immunological and renal parameters in patients with inactive and with active LN.** Data are expressed as the mean+/- standard deviation, A Mann Whitney test was used for comparisons between inactive and active LN, *: p < 0.05, **: p < 0.01 LN: lupus nephritis, UPCR: Urinary protein to creatinine ratio, eGFR: estimated glomerular filtration rate, BUN: Blood urea nitrogen, CRP: C-reactive protein, rSLEDAI: renal systemic lupus erythematosus disease activity index.
	Inactive LN (n = 17)	Active LN (n = 23)
Renal activity score (%)	0	61.27 ± 30.17^**
Immunological investigations
C3 (g/l)	0.89 ± 0.31	0.606 ± 0.312^**
C4 (g/l)	0.172 ± 0.097	0.11 ± 0.078^*
CH50 (%)	50.28 ± 37.23	50.18 ± 2.70
Anti-dsDNA (Ul/ml)	113.01 ± 156.71	185.64 ± 117.96^*
Renal investigations
Hematuria (RBC/mL)	47063 ± 69679	214436 ± 629323^**
Urinary casts (/mL)	0.83 ± 1.046	5.74 ± 8.568^**
Leukocyturia (GB/ml)	23.36 ± 23.17	140.78 ± 147.33^**
UPCR (g/mmol)	0.17 ± 0.11	0.36 ± 0.31^**
eGFR (ml/min)	99.82 ± 42.24	85 ± 28.00
Proteinuria (g/l)	1.1 ± 0.98	2.22 ± 2.62
Creatinuria (mmol/l)	7.85 ± 4.71	8.29 ± 5.02
BUN (mmol/l)	6.85 ± 5.69	7.67 ± 3.29
Serum Albumin (g/l)	30.74 ± 5.42	29.08 ± 5.78
CRP (mg/l)	6.16 ± 8.07	10.83 ± 19.13
Clinical assessment score
rSLEDAI	8.57 ± 4.67	12.76 ± 2.3^**
Renal chronicity score (%)	31.41 ± 27.85	9.86 ± 9.26^**

As expected, significant C3 (p < 0.01) and C4 (p < 0.05) hypocomplementemia and elevated anti-native DNA antibodies (p < 0.05) were found in the active LN group compared to inactive LN group. In the same way, hematuria, cylindruria, leukocyturia and UPCR were also significantly elevated in active LN compared to inactive LN (all, p < 0.01). For renal assessment, the rSLEDAI score was significantly elevated in active LN patients (p < 0.01) while the chronicity score that reflects the degree of renal fibrosis was significantly reduced compared to inactive LN (p < 0.01) (Table 1).

U-sCD163, but not U-sCD11b, discriminates between active and inactive lupus nephritis

We explored whether the levels of U-sCD163 and U-sCD11b could differentiate active from inactive LN in patients. U-sCD11b was correlated with UPCR (R = 0.347, p < 0.05) (Fig. 1A), but did not differ between LN groups (Figs. 1B and 1C). In contrast, U-sCD163 levels were significantly higher in patients with active LN than in patients with inactive LN (p < 0.05) (Fig. 2A). U-sCD163 levels were correlated with the renal activity score (R = 0.34, p < 0.05) (Fig. 2B), with leukocyturia (R = 0.326, p < 0.05) and with UPCR (R = 0.540, p < 0.001) (Figs. 2C and 2D).

The increase of U-sCD163 levels is associated with glomerular immune-complex deposits and correlated with inflammatory markers in PIL nephritis model

To investigate the involvement of U-sCD163 in the glomerular inflammation, we established a PIL nephritis mouse model presenting a glomerulonephritis and proinflammatory profile (Supplementary data, supplementary Fig. 1). We performed a longitudinal analysis in PIL nephritis mice model to study the evolution of U-sCD163 levels and the pro-inflammatory progression during the disease.

U-sCD163 was measured in mice before pristane induction (Day 0) and after 5 and 6 months. In the PIL group, U-sCD163 levels were steadily increased with disease progression, as objectivated by elevation IgG anC3 immune complexes deposits (Supplementary figure S1), with a significant elevation at 5 and 6 months after pristane induction compared to day 0 (Fig. 3A). In contrast, U-sCD163 levels were stable over time in the CO group (Fig. 3B). The comparison between PIL and CO groups showed that U-sCD163 was significantly elevated from the 5th month, the time-point before the glomerulonephritis onset and until euthanasia, which represents the most advanced disease stage (Fig. 3C). U-sCD163 levels, 6 months after pristane induction, were correlated with IFN-α (R = 0.71, p < 0.0001), CRP (R = 0.528, p < 0.01) and TNF-α (R = 0.82, p < 0.0001) levels (Figs. 3D, 3F and 3E).

U-sCD163 represents a marker for treatment response in PIL nephritis model

We investigated the effect of HCQ in PIL nephritis mouse model. Treatment with HCQ was administered either early, just after the injection of pristane, and for a duration of 6 months, or late, 3 months after pristane induction, for a duration of 3 months. Only early treatment with HCQ was associated with reduced IgG and C3 immune complex glomerular deposits compared to untreated PIL mice (Fig. 4A), although no difference was observed between groups in the level of proteinuria (Fig. 4B). In parallel with the reduction of immune complex glomerular deposits, U-sCD163 levels at 6 months were significantly decreased in mice who had received an early treatment with HCQ (Fig. 4C), leading us to propose the quantification of U-sCD163, as a biomarker of response to treatment.

We showed that U-sCD163 represent a biomarker for active LN reflecting the glomerular inflammation. Thus, the detection of U-sCD163 could be useful for following the disease activity and monitoring the response to treatment.

Although kidney biopsy is the gold standard method for LN diagnosis, non-invasive biomarkers are needed for the routine patient management. Macrophage surface biomarkers have been proposed as biomarkers of LN activity. In contrast to U-sCD11b, we showed that U-sCD163 levels are elevated in patients with active LN compared to patients with inactive LN. Our results are in agreement with recent studies in which U-sCD163 levels were elevated in patients with active LN^15,16. Consistently, we showed a correlation between U-sCD163 levels and the percent of glomeruli with active lesions (or renal activity score) and markers of glomerular lesions such as UPCR and active urinary sediment.

To better analyze the involvement of U-sCD163 in the kidney disease progression and in the associated pro-inflammatory response, we established a PIL nephritis mouse model and performed a longitudinal follow-up analysis to investigate the association of U-sCD163 levels and the disease evolution, with or without treatment. Importantly, the use of murine model will open the possibility for further interventional studies to better understand the mechanism of action of sCD163 which remains unclear in LN. The PIL mouse model is one of the few induced lupus models that can progress to glomerulonephritis, which allows to follow the development of glomerulonephritis and study the impact of therapeutic interventions in murine LN¹⁷. To the best of our knowledge, we are the first to investigate the levels of U-sCD163 in both human and murine LN. After disease induction, we showed an increase of U-sCD163 in association with IgG anC3 immune complexes deposits, even at a very early stage, together with an association with the augmentation of serum inflammatory markers including IFN-α, CRP and TNF-α. Moreover, we showed that treatment with HCQ, a well-known as immune modulator¹⁸, could prevent the elevation of U-sCD163 levels, in parallel with the reduction of IgG and C3 glomerular deposits. Interestingly, the level of proteinuria, which is another non-invasive, usually applied as marker of kidney damage, was not predictive of glomerular inflammation, contrary to U-sCD163.

Thus, we can propose U-sCD163 as a biomarker reflecting the glomerular inflammation. The interest of U-sCD163 was previously underlined by the fact that cells expressing CD163 are the most abundant cells detected in urine from LN patients compared to healthy donors¹⁵. In addition, transcriptomic analyses showed that the macrophage infiltrate in LN kidneys is predominantly composed of CD163⁺cells in active crescentic glomerulonephritis, proliferative glomerular lesions, and areas of tubulointerstitial injury^19,20. In addition to macrophages, a variety of cells express CD163, to a lesser extent, including monocytes²¹, neutrophils²², dendritic cells ²³ and non-myeloid cells ²⁴. All of them have been implicated as cellular key players in the pathogenesis of LN^25,26. Therefore, the high level of U-sCD163 observed in active LN patients could also be related to kidney infiltration by these cells’ populations. Nevertheless, our data led us to propose U-sCD163 as a biomarker reflecting the glomerular inflammation. Membrane CD163 is often associated with a functional polarization profile of macrophages, called M2 type, corresponding to an immunoregulatory profile²⁷. One can speculate that the progression of the glomerular inflammation is accompanied by a conversion of macrophages to the CD163 + phenotype and that urinary soluble CD163 may be cleaved in response to inflammatory stimuli including the PAMP lipopolysaccharide^28,29. In agreement, a marked increase in kidney cytokine levels were previously reported in human LN that stimulate IgG and type I IFN production and macrophage differentiation to CD163 + ³⁰. Taken together, our data indicate that U-sCD163 levels may reflect macrophage-dependent glomerular inflammation in LN, through the shedding of this protein from the surface of cells infiltrating glomeruli directly into the urine. We thus propose that U-sCD163 could be a promising non-invasive biomarker of LN, to detect kidney inflammation, monitor disease activity and response to treatment.

In conclusion, we propose U-sCD163, reflecting glomerular inflammation in LN, as a non-invasive biomarker for monitoring the disease activity. Although longitudinal studies on a larger cohort of patients with LN at different treatment time-points are needed, U-sCD163 could be useful to monitor response to treatment in patients.

Ethics statement

Urine samples were selected from the biological collection DC-2012-1704, authorized by the French Ministry of Health. This study was approved and registered by the APHM (Assistance Publique des Hôpitaux de Marseille) and fulfilled local requirement in terms of data collection, patients’ consent and data protection (RGPD).

The animal experimental protocol was approved by the animal experimentation ethics committee under reference number APAFIS #26184 and all animals handling, and procedures were performed in accordance with the French Decree n˚ 2013–118, 7 February 2013, European directive 2010/63/EU and ARRIVE guidelines for animal research.

Human study design and sample collection

Samples from patients aged ≥ 18 years, with a diagnosis of SLE with ≥ 4/11 American College of Rheumatology (ACR) criteria, and a kidney biopsy performed at the time of sampling, were used. Clinical data collection included urinary protein to creatinine ratio (UPCR), urinary sediment, serum creatinine and estimated glomerular filtration rate (eGFR) with the Modification of Diet in Renal Disease (MDRD) formula, blood urea nitrogen (BUN), serum albumin, C-reactive protein (CRP), complement fractions C3 and C4 and an anti-dsDNA assay. Kidney biopsies were classified according to the ISN/RPS 2003. Class III and IV LN with active lesions, with or without associated class V, were defined as active LN. Class I, II, isolated V or class VI LN, as well as class III-C and IV-C LN (with only chronic lesions), were defined as inactive LN. The percent of glomeruli with active lesions (renal activity score) and the percent of glomeruli with chronic lesions (renal chronicity score) were detailed. Clinical, demographic, and therapeutic data were collected retrospectively from the time of kidney biopsy and are summarized in Table 2.

Table 2

**Clinical, demographic, and therapeutic data of the study population.** Data are presented as numbers (percentage), ^a Data are expressed as the mean+/- standard deviation, LN: lupus nephritis, HCQ: Hydroxychloroquine, CTC: Corticosteroids, MMF: Mycophenolate mofetil, AZT: azathioprine, ISN/RPS: international Society of Nephrology/Renal Pathology Society, A: active lesion, C: chronic lesion.
		LN patients n = 40
Sex (male : female)		4 : 36
Age (years)^a		34.7 ± 11.70
Disease duration (years)^a		9.86 ± 8.90
Ethinicity
Caucasian (%)		18 (45%)
North african (%)		13 (32.5%)
African (%)		5 (12.5%)
Asian (%)		4 (10%)
Medications
HCQ (%)		28 (70%)
CTC (%)		32 (80%)
MMF (%)		7 (17.5%)
AZT (%)		5 (12.5%)
ISN/RPS CLASS
Active LN	III-A	4
	III-A + V	4
	IV-A	11
	IV-A + V	4
Inactive LN	II	3
	III-C	1
	IV-C	1
	V	10
	VI	2

Experimental design of pristane-induced lupus mouse model

Nine weeks old female BALB/cByJ mice were obtained from Charles River Laboratories (Charles River Laboratories, L’Arbresle, Lyon, France). Animals were housed in a controlled temperature and pressure environment and house-kept in cages with water and food ad libitum enriched with cardboard house with cotton squares for nests. Immunological, inflammatory, and renal analysis were obtained for urine and serum samples collected before disease induction (day 0) and at six months to validate LN induction. Mice were randomly divided into four groups : i) pristane-induced-lupus (PIL) (n = 14) that received a single intra-peritoneal (IP) injection of 500 µl of sterile pristane oil (2, 6, 10, 14-tetramethylpentadecane, Sigma Aldrich, MO, USA) according to Satoh et al³¹, ii) control group (CO) (n = 13) that received a single IP injection of 500 µl of sterile phosphate buffered saline (PBS, Sigma Aldrich) at day 1, iii) 6 months hydroxychloroquine treated group (HCQ-6M) (n = 7) that received a single IP injection of 500 µl of sterile pristane oil at day 1 and daily oral gavage of 15mg/kg of HCQ from day 2 until euthanasia and iv) 3 months HCQ treated group (HCQ-3M) (n = 8) that received a single IP injection of 500 µl of sterile pristane oil at day 1 and daily oral gavage of 15mg/kg of HCQ from 3 months post-induction until euthanasia. The experimental design is illustrated in Fig. 5.

Immunoassays

Serum antinuclear antibodies detection (ANA) was determined by indirect immunofluorescence method using commercial slides containing HEp-2 cells (Kallestad HEp-2 Cell Line Substrate, 12-wells slides, Bio-Rad Laboratories, Hercules, CA) according to the manufacturer instructions. Serum antibodies against double stranded DNA (ds-DNA) was measured by ELISA method using mouse anti-dsDNA IgG-specific ELISA kit (Mybiosource, San Diego, CA, USA) according to manufacturer instruction’s. Levels of interferon (IFN)-α (PBL assay science, Piscataway, NJ, USA), tumor necrosis factor (TNF)-α (Aviva system biology, USA) and C-reactive protein (CRP) (Aviva system biology) were measured using commercially available ELISA kits according to manufacturer instructions. The detection range was 1.56-50 ng/ml for anti-dsDNA IgG, 1.19-76 pg/ml for IFN-α, 16-2000 pg/ml for TNF-α and 1-25ng/ml and 1–25 ng/ml for CRP Fresh collected urine samples were also analyzed to determine level of proteinuria using protein detection reagent strips (Uristix from Siemens Medical Solutions Diagnostics) and was scored on a scale of 0–4, where 0 = none, 1 = 30 mg/dl, 2 = 100 mg/dl, 3 = 300 mg/dl, and 4 = 1000 mg/dl.

Murine kidney biopsies analysis

Kidney tissues were collected and snap frozen in liquid nitrogen after euthanasia and then stored at -80°C for immunofluorescence investigation. Four µM sections were realized and immune complex deposition was investigated using FITC-conjugated goat anti-mouse IgG (1:100 dilution, Invitrogen, USA) and anti-mouse C3 (Mybiosource). The slides were observed under LSM800 Airyscan confocal fluorescent microscope (Zeiss) using 63x oil objective.

Assays of U-sCD11b and U-sCD163

Levels of human U-sCD11b and U-sCD163 were measured in urine samples after centrifugation at 2000 rpm for 10 min using ELISA assay kits according to the manufacturer’s instructions (MBS702254 and DY1607 DuoSet; R&D Systems, Minneapolis, MN and USA respectively). U-sCD11b and U-sCD163 values were normalized to urine creatinine.

Mouse urine samples were centrifuged at 1000 rpm for 10 minutes, and supernatant was used to evaluate level of U-sCD163 using commercial ELISA kit (Mybiosource) according to the manufacturer instructions.

Statistical analysis

All data were analyzed using Prism 9.2 (GraphPad Software, La Jolla, CA). Continuous variables such as age and activity score are presented as means ± SD. Biomarker assays are described as mean ± SD concentration. The comparison between groups was analyzed by Mann-Whitney and one-way-ANOVA test. The analysis of U-sCD163 in mice was performed using a mixed model analysis for repeated measurements (before induction, at 5 months, and 6 months post-induction). Comparisons between groups at each timepoint were performed using Tukey-Kramer accounting for multiple comparisons. Non-parametric spearman correlation was used to investigate associations between two variables. A two-tail P value less than 0.05 was considered statistically significant.

Data Availability statement

The data presented in this study are included in the manuscript and supplementary materials. Additional information requests can be directed to the corresponding author.

Informed consent statement

Written informed consent was obtained from all patients before sample collection.

Author’s contributions

Conceptualization: ET, NB, NJC and JLM. Methodology: ET, MM, MT, and AB. Analysis: ET, GP. Validation: SM, NB and JLM. Writing and original manuscript preparation: ET, NB and SM. Review and editing: all authors. Final manuscript validation: ET, SM, NJC, NB, and JLM. Supervision: NB, JLM and PH. Funding acquisition: PH and JLM. All authors discussed the results and commented on the manuscript. All authors contributed to the article and approved the submitted version.

Funding

This research did not receive any specific grant from any funding agencies in the public, commercial, or non-profits sectors.

Conflict of interest

NJC received speaking and expertise fees from OTSUKA and VIFOR.

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No competing interests reported.

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Urinary soluble CD163: a non-invasive biomarker to monitor lupus nephritis

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Abstract

Figures

Introduction

Results

Clinical and biological characteristics of SLE patients

U-sCD163, but not U-sCD11b, discriminates between active and inactive lupus nephritis

U-sCD163 represents a marker for treatment response in PIL nephritis model

Discussion

Materials And Methods

Ethics statement

Human study design and sample collection

Experimental design of pristane-induced lupus mouse model

Immunoassays

Murine kidney biopsies analysis

Assays of U-sCD11b and U-sCD163

Statistical analysis

Declarations

References

Additional Declarations

Supplementary Files

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