Introduction: Presence of subclinical intestinal inflammation has repeatedly been shown in IgA nephropathy (IgAN) and the degree of histological inflammation has correlated with abnormal urinary findings. There is lack of noninvasive biomarkers evaluating the presence of subclinical intestinal damage in IgAN. We conducted this study hypothesizing that selected biomarkers regarded as indirect markers of intestinal damage could be elevated in IgAN. Methods: Eighty-five primary IgAN patients (median age 55 years, 54% men) participated in this single-center study in Tampere, Finland. None had end-stage kidney disease or previously diagnosed enteropathies. Celiac disease was excluded with serum transglutaminase 2 antibody (TG2Ab) and endomysial antibody tests and inflammatory bowel disease with fecal calprotectin. Intestinal damage was evaluated from sera with analyses of intestinal fatty-acid binding protein (I-FABP), soluble cluster of differentiation molecule 14 (sCD14), and lipopolysaccharide binding protein. Fourteen people suffering from dyspepsia and 15 healthy people served as controls. Results: I-FABP levels among IgAN patients were higher than in the healthy controls (median 830 pg/mL vs. 289 pg/mL, p < 0.001). Also, sCD14 was increased in IgAN patients compared to dyspepsia controls. Although TG2Ab levels were within the normal range among IgAN patients, they were higher than in the healthy controls (median 1.3 U/mL vs. 0.6 U/mL, p < 0.001). Conclusions: Elevated serum levels of I-FABP were present in primary IgAN patients without known enteropathies. Serum I-FABP may indicate the presence of subclinical intestinal damage. These findings encourage further investigation into the role of the intestine in the pathophysiology of IgAN.

Shared risk loci in genes involved in the intestinal mucosal integrity in IgA nephropathy (IgAN) and inflammatory bowel disease (IBD) are an example of the intestine-renal connection [1, 2]. IBD, including ulcerative colitis and Crohn’s disease (CrD), are chronic inflammatory disorders of the gastrointestinal (GI) tract [3]. Both the prevalence of IgAN in IBD and conversely the prevalence of IBD in IgAN are increased [4‒6]. The same applies to IgAN and celiac disease (CeD) [7‒9], an immune-mediated enteropathy induced by the ingestion of cereals containing gluten [10].

Increased reactivity to dietary proteins has been observed in IgAN, a finding associated with subclinical intestinal inflammation in the absence of concomitant CeD or IBD [11]. Orally administered protein antigens have been able to induce a mucosal immune response that resulted in mesangial IgA deposits in mice [12]. Likewise, mesangial IgA deposits could be induced in mice by oral immunization with wheat gluten, gliadin [13]. On the other hand, gliadin exacerbated intestinal inflammation in a mouse model of IgAN [14]. An abundance of inflammatory cells has also been found in the duodenal mucosa of IgAN patients, and the degree of intestinal inflammation has correlated with the severity of proteinuria and hematuria [15‒17]. Interestingly, IgAN patients may also experience mild but notable GI symptoms more often than healthy people, again after the exclusion of known enteropathies [18].

Structural and functional alterations of the intestinal barrier have also been detected in end-stage kidney disease (ESKD) [19]. Uremia results in the depletion of key proteins of intestinal epithelial tight junctions in rats [20]. The ensuing increase in intestinal permeability (IP) has been acknowledged to contribute to systemic inflammation associated with ESKD [19]. In a small study, increased IP was shown to be present in IgAN and other primary glomerulonephritides (GN) well before manifest ESKD [21]. Interestingly, deterioration of kidney function has been shown to be faster in IgAN patients with increased IP than in those with normal IP [22].

Intestinal damage and inflammation can be measured indirectly [23]. Fecal calprotectin (F-Calpro) is a sensitive biomarker to detect gut inflammation in IBD [24]. Serum intestinal fatty-acid binding protein (I-FABP) is a biomarker of enterocyte damage, and therefore, I-FABP has been used as a surrogate marker of increased IP [25, 26]. Serum lipopolysaccharide binding protein (LBP) and soluble cluster of differentiation 14 (sCD14) molecule are endotoxin-related markers, which are most likely elevated in response to bacteria translocating through the inflamed and leaky gut wall [27].

In light of our previous finding of an excess of GI symptoms among IgAN patients [18], in the present study we first excluded the presence of undiagnosed CeD or IBD by measuring serum celiac autoantibody and F-Calpro levels. Thereafter, the levels of the above-mentioned three potential intestinal biomarkers were measured to test for the presence of subclinical intestinal damage in IgAN. The results were compared to those of patients suffering from dyspepsia and healthy people.

Design and Study Population

This is a single-center cross-sectional study focusing on primary IgAN patients and carried out in 2019 and 2020 at Tampere University Hospital (TAUH) and Tampere University, Finland. The definition of IgAN was based on clinical details and on the presence of glomerular IgA as the sole or predominant immunofluorescence finding [28]. The predefined exclusion criteria were as earlier described [18]: death, progression to ESKD (defined as estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m2, onset of maintenance dialysis or kidney transplantation), age of under 18 or over 80 at recruitment to the study, previously diagnosed chronic enteropathy (CeD or IBD), moving to another hospital district, major GI surgery performed (hemicolectomy or more of the colon removed), or other obvious reason for exclusion (missing contact information, short life-expectancy for any reason, or a labile psychic disorder). A total of 104 biopsy-proven IgAN patients diagnosed between 1980 and 2018 responded to the posted questionnaires eliciting presence of GI symptoms, quality of life and basic background information such as current smoking status and alcohol consumption [18]. Blood and fecal samples were taken from 85 volunteer IgAN patients, who thus became enrolled in the present study, forming the study group of IgAN patients.

Dyspepsia controls and healthy controls were participants from our earlier studies [29, 30]. The dyspepsia controls had undergone gastroscopies with normal findings, excluding CeD. The healthy controls were relatives of patients with CeD but had been tested negative for CeD. No other clinical information except age and sex was available for these two control groups.

Patient Sampling

Blood samples were taken from all 114 participants. Fecal samples were taken from 57 IgAN patient volunteers. Blood samples were centrifuged and serum stored frozen (−80°C) until the measurements were performed. Fresh fecal samples were collected in a sterile container and immediately stored at −80°C.

Celiac Serology and Fecal Calprotectin

Celiac autoantibodies were determined from the serum samples by measuring IgA class transglutaminase 2 antibodies (TG2Ab) and endomysial antibodies (EmAs). TG2Ab levels were determined according to manufacturers’ instructions with EliA Celikey assay (ThermoFisher Scientific, Waltham, MA, USA, cut-off for positivity 7.0 U/mL) from the serum samples. EmA was determined by an in-house indirect immunofluorescence method using human umbilical cord as substrate [31]. A serum dilution of 1:≥5 was considered positive.

F-Calpro was measured by ELISA kit (Calpro AS, Oslo, Norway) following instructions provided by the manufacturer. The cut-off value was 50 µg/g.

Intestinal Damage Markers

Serum levels of I-FABP, sCD14 and LBP were determined with commercially available kits following the instructions provided by the manufacturer. For the I-FABP ELISA kit (Hycult Biotech, Uden, The Netherlands) the detection limit was 47 pg/mL, for the sCD14 ELISA kit (Hycult Biotech, Uden, The Netherlands) 1.56 ng/mL and for the LBP ELISA kit (Hycult Biotech, Uden, The Netherlands) 4.4 ng/mL.

Evaluation of GI Symptoms

For the systematic evaluation of current GI symptoms, IgAN patients had completed the self-administered, structured and well-validated Gastrointestinal Symptom Rating Scale (GSRS) questionnaire [32‒34]. This questionnaire evaluates five sub-dimensions of GI symptoms: indigestion, diarrhea, abdominal pain, reflux, and constipation. The results have been published in detail elsewhere [18].

Clinical Data

The clinical data for the IgAN patients was collected retrospectively from the medical records of TAUH between 2019 and 2020. Data on medications taken and treatment of the kidney disease was collected. Laboratory test results regarding kidney function were collected from a 3-year period preceding the study recruitment. Kidney function was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation [35]. Current kidney function was evaluated from the latest creatinine measurement taken at the stable phase of kidney disease, not more than 1 year before study enrollment. eGFR <60 mL/min/1.73 m2 was categorized as impaired kidney function. Annual change in eGFR was determined by dividing the differences between eGFR values from the time of the kidney biopsy and the latest creatinine measurement by years from the kidney biopsy. Albuminuria was evaluated based on the most recent urinalysis, not more than 1 year before study enrollment. Category A3 albuminuria was regarded as present albuminuria [36]. Available methods were the albumin dipstick test (+ or higher deemed positive), the albumin-to-creatinine ratio (>30 mg/mmol deemed positive), or collected urine (>300 mg/24 h deemed positive). Complementary background information, like alcohol consumption [37], was surveyed in conjunction with the GSRS questionnaire for IgAN patients.

Statistical Methods

The data are presented as medians and interquartile ranges (IQR) for most of the continuous variables and as percentages for the categorical variables. Groups were compared using the χ2 test, Fisher’s exact test or the Mann-Whitney U-test as appropriate. Spearman’s correlation coefficient (rS) was used to evaluate correlations between continuous variables.

All tests were two-sided, and p values <0.05 were considered statistically significant. All statistical testing was performed using SPSS version 27 (IBM SPSS, Armonk, NY, USA).

Ethical Consideration

The study protocol was approved by the Ethics Committee of Tampere University Hospital (R18215). All study participants provided written informed consent.

Study Population

Median age of the 85 IgAN patients was 55 years (IQR: 46–68 years) and a minor male majority (54%) was present (Table 1). The fourteen dyspepsia controls were 59 (IQR: 34–67) years old and 21% of them were males. The fifteen healthy controls were 57 (47–63) years old and 47% of them were males. The three groups did not differ in age (p = 0.861) or sex distribution (p = 0.075). Data on albuminuria were available for 48 (56%) IgAN patients and it had most often been quantified with the albumin-to-creatinine ratio (in 31 cases). Albuminuria was present in 11 patients (23%).

Table 1.

Clinical characteristics of the IgA nephropathy (IgAN) patients

Patient characteristicsIgAN patients, n = 85
Male gender, % 54 
Current age, years 55 (46–68) 
Current body mass index, kg/m2 29 (25–33) 
Current smoker, % 10 
Risky alcohol usea, % 25 
Medication during the year before the study, % 
 Blood pressure lowering 79 
 Lipid lowering 42 
 Glucose lowering 12 
 Immunosuppressive 
 Antibiotics 45 
 Proton pump inhibitor 25 
Time since diagnostic kidney biopsy, years 11 (6–20) 
Current kidney functionb 
 Estimated glomerular filtration rate (eGFR), mL/min/1.73 m2 63 (49–82) 
 eGFR <60 mL/min/1.73 m2, % 43 
Annual change of eGFR, mL/min/1.73 m2c −0.7 (−2.1 to +0.5) 
Patient characteristicsIgAN patients, n = 85
Male gender, % 54 
Current age, years 55 (46–68) 
Current body mass index, kg/m2 29 (25–33) 
Current smoker, % 10 
Risky alcohol usea, % 25 
Medication during the year before the study, % 
 Blood pressure lowering 79 
 Lipid lowering 42 
 Glucose lowering 12 
 Immunosuppressive 
 Antibiotics 45 
 Proton pump inhibitor 25 
Time since diagnostic kidney biopsy, years 11 (6–20) 
Current kidney functionb 
 Estimated glomerular filtration rate (eGFR), mL/min/1.73 m2 63 (49–82) 
 eGFR <60 mL/min/1.73 m2, % 43 
Annual change of eGFR, mL/min/1.73 m2c −0.7 (−2.1 to +0.5) 

Values are medians (interquartile ranges) unless otherwise indicated. aFor women 5 or more points, for men 6 or more points in the Alcohol Use Disorders Identification Test (AUDIT-C).

bData available from 68 IgAN patients.

cData available from 64 IgAN patients.

Celiac Serology and Fecal Calprotectin

All except 1 IgAN patient had TG2Ab below the cut-off level, and the one exceeding the cut-off level had a borderline elevation (7.1 U/mL) only. None of the IgAN patients were EmA positive. TG2Ab was higher in IgAN patients (median 1.3, IQR: 0.8–1.9 U/mL) than in healthy controls (0.6, 0.3–0.7 U/mL, p < 0.001) but no difference was seen when IgAN patients were compared with dyspepsia controls (1.6, 1.1–3.0 U/mL, p = 0.077). F-Calpro was available for 57 IgAN patients and was below the detection level in all cases.

Intestinal Damage Markers

Median serum I-FABP level among IgAN patients was 830 pg/mL (IQR: 475–1,378 pg/mL), a value that was clearly higher than among the healthy controls (Table 2). Soluble CD14 was lowest among the dyspepsia controls. LBP did not differ between the three groups (Table 2). I-FABP and TG2Ab did not correlate among IgAN patients (rS = 0.142, p = 0.196).

Table 2.

Test results of the indirect markers for intestinal damage, presented as medians and interquartile ranges

IgAN patientsDyspepsia controlsHealthy controls
n = 85n = 14n = 15
I-FABP 830 (475–1,378) 510 (380–724) 289 (199–568)* 
sCD14 2.9 (2.4–3.6) 1.6 (1.0–2.3)* 2.8 (2.5–3.7) 
LBP 11.7 (8.2–18.3) 15.1 (10.5–25.2) 14.8 (7.6–21.4) 
IgAN patientsDyspepsia controlsHealthy controls
n = 85n = 14n = 15
I-FABP 830 (475–1,378) 510 (380–724) 289 (199–568)* 
sCD14 2.9 (2.4–3.6) 1.6 (1.0–2.3)* 2.8 (2.5–3.7) 
LBP 11.7 (8.2–18.3) 15.1 (10.5–25.2) 14.8 (7.6–21.4) 

IgAN, IgA nephropathy; I-FABP, intestinal fatty-acid binding protein, pg/mL; sCD14, soluble cluster of differentiation molecule 14, μg/mL; LBP, lipopolysaccharide binding protein, μg/mL.

*p < 0.05 compared to IgAN patients.

Serum I-FABP was higher in IgAN patients with impaired kidney function than in patients with preserved kidney function (median 1,100 pg/mL, IQR: 868–1,949 pg/mL vs. 650 pg/mL, IQR: 419–880 pg/mL, p < 0.001). Nevertheless, even IgAN patients with preserved kidney function had higher I-FABP levels than healthy controls (Fig. 1). When IgAN patients were further limited to those with eGFR above 80 mL/min/1.73 m2, no statistically significant difference was found between their I-FABP levels (median 578 pg/mL, IQR: 260–768 pg/mL) and those of healthy controls (p = 0.056). Serum I-FABP level had a moderate inverse correlation with current eGFR (rS = −0.598, p < 0.001) but not with the annual change in eGFR (rS = 0.095, p = 0.454). Likewise, serum I-FABP had a moderate positive correlation with the albumin-to-creatinine ratio (rS = 0.546, p = 0.001).

Fig. 1.

Intestinal fatty-acid binding protein (I-FABP) levels in IgAN patients grouped on the basis of kidney function and in dyspepsia controls and in healthy controls.

Fig. 1.

Intestinal fatty-acid binding protein (I-FABP) levels in IgAN patients grouped on the basis of kidney function and in dyspepsia controls and in healthy controls.

Close modal

Soluble CD14 was also higher in IgAN patients with impaired kidney function than in patients with preserved kidney function (3.4 μg/mL, IQR: 2.6–3.9 μg/mL vs. 2.7 μg/mL, IQR: 2.3–3.4 μg/mL, p = 0.003). Soluble CD14 correlated inversely with current eGFR (rS = −0.332, p = 0.006), but did not correlate with the annual change in eGFR (rS = −0.029, p = 0.822). There was no difference in serum LBP levels between IgAN patients with reduced versus preserved kidney function (median 13.7 μg/mL, IQR: 10.6–19.5 μg/mL vs. 11.0 μg/mL, IQR: 7.1–18.7 μg/mL, p = 0.165).

GI Symptoms and Damage Markers

Serum I-FABP levels did not correlate with total GSRS score in patients with IgAN (rS = −0.106, p = 0.393). Nor did the I-FABP levels correlate with any of the GSRS subscores (data not shown). Serum TG2 antibody, sCD14, and LBP levels did not correlate with either total GSRS score or GSRS subscores (data not shown).

This study focused on a well-defined population of primary IgAN patients, in whom known enteropathies, IBD and CeD, were excluded by the negative patient history and negative fecal calprotectin and serum CeD serology tests. Importantly, the patients had not progressed to ESKD, during which intestinal barrier function may be impaired due to uremia and the microbiome may be altered [19]. Most of the present patients had preserved kidney function, and therefore, our results can be interpreted without the confounding interference caused by intestinal damage or increased IP present in ESKD.

In an earlier study, serum I-FABP among untreated CeD patients was essentially on the same level as it was among the IgAN patients in the present study, even including those IgAN patients with preserved kidney function [26]. Previous studies have reported increased numbers of inflammatory cells, including intraepithelial lymphocytes in the intestines of IgAN patients, most likely as a sign of gut inflammation [15‒17]. In CeD, intraepithelial lymphocytes have an important role in inducing epithelial cell damage [10]. Furthermore, serum I-FABP levels have been shown to correlate with intraepithelial lymphocyte counts [26]. The finding of elevated I-FABP in the present study may thus be driven by a similar process. However, there is no definitive noninvasive test available to verify the presence of gut inflammation. The fact that LBP and sCD14 were not elevated among IgAN patients could be explained by what these tests measure. LBP and sCD14 are primarily regarded as endotoxin-related markers and likely elevated in response to bacteria translocating through the inflamed and leaky gut wall, as in active CrD [27]. Inflammation in active CrD is in transmural form, and thus, probably a type of intestinal damage not seen in IgAN would be needed to cause a clear elevation in the serum levels of these two tests.

I-FABP is thought to be readily excreted by the kidneys and its serum level rises during declining kidney function. This correlation, however, was weak when studied in patients admitted for elective cardiac surgery (rS = −0.313, p = 0.002) [38]. As far as we know, no other studies of the kidney function and I-FABP levels have been published. Our finding of higher I-FABP in IgAN patients with kidney failure compared to IgAN patients with preserved kidney function could at least partly be associated with the loss of kidney function and the ensuing cumulation of I-FABP. Nevertheless, a similar explanation for the higher I-FABP levels in IgAN patients with preserved kidney function compared to healthy controls should be debated as significant loss in kidney clearance in patients with eGFR above 60 mL/min/1.73 m2 is unlikely. The lack of statistical significance in the difference between the I-FABP levels of IgAN patients with eGFR above 80 mL/min/1.73 m2 and those of healthy controls should not immediately be taken as a proof of only kidney function affecting the I-FABP levels. On the one hand, the number of patients in both groups was small. On the other hand, one could speculate that these patients may have had less active intestinal injury and accordingly better kidney function, especially as the I-FABP levels did correlate with the amount of albuminuria too.

Li and colleagues measured IgAN patients’ levels of zonulin, another possible marker of intestinal damage, and found the levels to be higher than those of healthy people [39]. Elevated small intestinal permeability was found to be a common phenomenon in various glomerular diseases in a small pilot study, including 35 IgAN patients. It was concluded that elevated intestinal permeability was not specific to IgAN [40]. However, this was a single-center study, in which fifteen out of the eighteen non-IgAN control patients were receiving immunosuppressive therapy.

TG2 is regarded as one of the molecular links between IgAN and CeD [41]. Binding of IgA to the transferrin receptor (CD71) is facilitated and amplified by TG2, the autoantigen of CeD [42]. CD71 is a major IgA receptor on mesangial cells and is overexpressed on enterocytes during active CeD [43, 44]. TG2-targeted IgA deposits have been found in kidney biopsies of gluten-consuming IgAN patients and elevated serum TG2Ab levels have also been reported in IgAN [9, 45, 46]. Although the TG2Ab levels were below the diagnostic cut-off in all except 1 IgAN patient in the present study, the levels were higher than in healthy people. In an earlier study, elevated TG2Ab levels predicted future CeD years before the actual onset of the disease in comparison with those people who did not develop CeD [47]. Whether IgAN patients with negative screening results should be rescreened for CeD is an open question. Of note, EmA-positivity among IgAN patients without CeD has only been reported in one study [48], whereas a few reports, including the present study, have found IgAN patients to be without EmA-positivity [45, 49, 50].

The subjective GI symptoms did not correlate with any of the intestinal damage markers. Most likely the origins of the GI symptoms were multifactorial, and as such, GI symptoms cannot be regarded as very relevant in the evaluation of the role of the intestine in the pathogenesis of IgAN [18]. On the other hand, the lack of specific symptoms fits with the concept of subclinical injury.

There are some important limitations that should be emphasized regarding the present study. All study participants were of Caucasian origin. There was no control group with another form of primary glomerulonephritis, which leaves uncertainty whether elevated I-FABP is present in kidney diseases in general or if the phenomenon is associated with IgAN only. I-FABP originates in the small intestine, predominantly in the jejunum, and only to a lesser extent in the colon [38]. Thus, I-FABP as an injury marker does not cover the whole of the intestine. There are also notable strengths in the present study. All the patients had biopsy confirmed primary IgAN. Exclusion of known enteropathies enabled us to focus on the study hypothesis of IgAN patients having subclinical intestinal damage. The patient sample was also relatively large when compared with previous IgAN studies [15, 16, 22, 50].

To conclude, our finding of elevated levels of I-FABP in IgAN patients, even in patients with preserved kidney function, might reflect the presence of subclinical intestinal damage in IgAN. The present results support the view that the search for an intestinal process as part of the pathogenesis of IgAN should continue. This study presented a new perspective on possible subclinical intestinal injury in IgAN, and thus, it is of the utmost importance to verify the results in IgAN patients of different ethnicities and in larger populations. Also, more research is needed on the role of kidney function in different biomarkers of intestinal injury, including I-FABP.

We thank Atte Kukkurainen for study co-ordination and patient sampling.

This study was conducted in accordance with the ethical principles of the World Medical Association Declaration of Helsinki. The study protocol was reviewed and approved by the Ethics Committee of Tampere University Hospital (approval number: R18215). All study participants provided written informed consent.

The authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The results presented in this paper have not been published previously in whole or in part, except in abstract form. We have no conflicts of interest to declare.

This study was supported by the Academy of Finland, the Competitive State Research Financing of the Expert Responsibility Area of Tampere University Hospital (9AA026, 9AA052, 9AB025, 9T039, MK303), the Finnish Coeliac Society, the Finnish Kidney Foundation, and the Sigrid Juselius Foundation. The funding sources were not involved in the study design; in the collection, analysis, and interpretation of the data; in the writing of the report; and in the decision to submit the article for publication.

Jussi Pohjonen participated in the design of the study, collected the data, analyzed and interpreted the data, drafted and revised the article, and approved the final manuscript. Katri Kaukinen, Heini Huhtala, Katri Lindfors, and Satu Mäkelä participated in the design of the study, analyzed and interpreted the data, provided intellectual content of critical importance to the study, and read, revised, and approved the final manuscript. Ilkka Pörsti and Jukka Mustonen participated in the design of the study, provided intellectual content of critical importance to the study, and read, revised, and approved the final manuscript.

The data underlying this article will be shared on reasonable request to the corresponding author.

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