Mannose binding lectin level and polymorphism in patients on long-term peritoneal dialysis
Man Fai Lam,
Joseph C. K. Leung,
Colin C. S. Tang,
Wai Kei Lo,
Kai Chung Tse,
Terrance P. Yip,
Sing Leung Lui,
Tak Mao Chan and
Kar Neng Lai
Nephrology Division, Department of Medicine, University of Hong Kong, Pokfulam Road, Hong Kong
Correspondence and offprint requests to: Professor K. N. Lai, Department of Medicine, University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong. Email: knlai{at}hkucc.hku.hk
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Abstract
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Background. Infection is a leading cause of mortality and morbidity in patients with end-stage renal disease. The increased susceptibility to infection is probably secondary to the impaired immune defence in uraemia and other co-morbid factors such as diabetes mellitus. Peritonitis remains the most common and major complication in the treatment modality of peritoneal dialysis (PD) for uraemic patients. Mannose binding lectin (MBL) is a calcium dependent C-type lectin that acts as an important first line defence mechanism against infection by its capability to activate the complement system and enhance phagocytosis.
Methods. We examined whether serum concentration of MBL and the point mutation of MBL may act as a risk factor in PD-related peritonitis. We studied four groups of dialysis patients: PD patients with two or more episodes of peritonitis, peritonitis-free PD patients, haemodialysis (HD) patients not previously on PD, and HD patients who were converted from PD due to technique failure following peritonitis-related abdominal adhesion.
Results. Both homozygous and heterozygous patients had profoundly reduced serum level of MBL. The codon 54 point mutation rate amongst our dialysis patients was comparable with that of healthy subjects. Dialysis patients had a significantly lower serum level of MBL than healthy controls independent of the MBL gene mutation or the mode of dialysis treatment. Patients on PD with codon 54 point mutation were found to have a lower serum MBL level compared with HD patients with similar MBL gene mutation. However, we found no difference in the serum MBL level or frequency of codon 54 point mutation between four groups of dialysis patients.
Conclusions. Dialysis patients have lower MBL levels that may increase the susceptibility of infection. However, the existence of other risk factors such as connection technique, nasal bacterial carriers, bowel pathology and personal hygiene precludes the MBL level as the sole primary factor for peritonitis in patients on maintenance PD treatment.
Keywords: gene mutation; haemodialysis; mannose binding lectin; peritoneal dialysis; peritonitis
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Introduction
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Peritonitis remains the most common and major complication in the treatment modality of peritoneal dialysis (PD) for patients with end-stage renal disease. It is the major cause of hospitalization, technique failure and mortality [1]. Although the main source of bacteria is the skin or the tunnel tract, peritonitis may occasionally arise from the transmural spread of enteric microorganisms, even after an endoscopic procedure [2,3]. Other risk factors associated with the development of peritonitis include poor technique and nasal carriers of Staphyloccous aureus. Despite different educational programme involving repeated training and technique assessment, the peritonitis rate due to bacterial entry via the catheter or the bowel has not been much further reduced [4]. What remains unexplored is any intrinsic factor that predispose patients to the development of peritonitis.
Mannose-binding lectin (MBL), a calcium dependent C-type lectin, acts as an important first line defence mechanism to protect the body from infection by its capability of activating both classical and alternative pathways of complement system and enhance phagocytosis [5]. This lectin is capable of binding a broad range of microorganisms including Gram-negative and Gram-positive bacteria, mycobacteria and viruses [6]. Previous studies have shown point mutation at codon 52, 54 or 57 of the MBL gene is associated with low serum level of MBL [7]. Congenital deficiency of MBL may confer increased risk of infection in adults because of impaired phagocytosis by polymorphonuclear leucocytes secondary to defective opsonization [8]. Most intriguingly, low serum level of MBL is associated with a higher incidence of spontaneous bacterial peritonitis in patients with chronic viral hepatitis [9]. In this study, we examine whether serum concentration of MBL and the point mutation of MBL may act as a risk factor in PD-related peritonitis.
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Subjects and methods
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Patients
Patients on long-term continuous ambulatory peritoneal dialysis (CAPD) or haemodialysis (HD) were recruited from two dialysis centres during the period between October 2003 and March 2004. Patients on CAPD were screened for clinical events of PD-related peritonitis since the commencement of PD treatment from their hospital records and the regional renal registry. Peritonitis is defined as turbid PD fluid with a total white cell count >100/mm3 in which more than 50% are polymorphonuclear cells. Relapsing peritonitis, defined as development of peritonitis from the same organism within 2 weeks of completion of antibiotics, was counted as the same peritonitis episode.
Baseline data including age, sex, body weight, underlying renal disease, CAPD system and presence of co-morbid diseases such as diabetes mellitus (DM), cardiovascular disease (CVD), viral hepatitis B and hepatitis C were recorded. CVD was defined as presence of ischaemic heart disease, congestive heart failure, cerebrovascular disease or peripheral vascular disease. The body mass index (BMI) was computed from patients weight in kg divided by the square of their height in metres [BMI = weight (kg)/height (m2)]. The latest adequacy dose, residual renal function and nutritional markers were recorded.
Existing patients on CAPD with two or more episodes of peritonitis throughout the dialysis period were recruited as the repeated peritonitis (RP) group while patients without any history of peritonitis were recruited as the peritonitis-free (FP) group. However, the FP patients were only included when they had been on PD for >2 years, making reference to the average peritonitis rate of once every 24 patient months in our dialysis centres at the time of commencement of this study. Patients on long-term HD were also recruited for study. HD patients who developed CAPD technique failure due to abdominal adhesion secondary to peritonitis were recruited and classified as the technique failure (TF) group. Other HD patients (not previously on PD) were recruited as the HD control group (HC). Thirty-six healthy subjects of the same ethnic origin were recruited as controls. This study was approved by the ethics committees of our institutions and all patients gave written informed consent.
Blood and PD fluid collection
Samples of overnight-dwell PD fluid from the FP and RP groups were collected for measurement of MBL level. Blood samples were taken immediately after collection of overnight-dwell PD fluid for serum MBL, serum albumin and plasma alanine aminotransferase. DNA for MBL point mutation analysis was extracted from blood samples using the NucleoSpin Blood kit (Macherey-Nagel, Easton, PA, USA). For patients with a major illness or any major infection including peritonitis during the study period, blood and PD fluid samples were collected at least 4 weeks after recovery from the event. Serum samples were collected from HD patients 1 day prior to dialysis treatment.
Measurement of serum and peritoneal levels of MBL
Serum MBL level was measured by a ligand-lectin solid-phase enzyme-linked immunoassay (ELISA) (Cell Sciences, Norwood, MA, USA). Samples and standards were incubated in microtiter wells coated with mannan. During incubation, the mannan binding property of functional MBL was used to capture MBL by solid bound mannan. Unbound protein present in the sample was removed by washing. Biotinylated antibody to human MBL was then added to the wells for binding the mannan-bound MBL. Streptavidinperoxidase conjugate was applied to the wells and reacted specifically with the biotinylated tracer antibody. Colour developed proportionally to the amount of MBL present in the sample. The enzyme reaction was finally stopped by the addition of citric acid and the absorbance at 450 nm was measured with a spectrophotometer. The detection limit of the kit is 0.41 ng/ml with an intra-batch CV of 10.9%.
Genotyping for MBL mutation
Point mutations of the MBL gene were detected by the polymerase chain reaction (PCR)-restriction fragment length polymorphism. Codon 54 and codon 57 point mutation were detected by PCR amplification at exon 1 DNA from individuals with differing genotypes, giving distinct gel electrophoretic patterns after MboII and BanI digestion, respectively. A DNA product of 328 bp was first generated using the 20mer oligonucleoside, 5'-DGTAGGACAGAGGGCATGCTC-3' (bases 164 of the upper strand) and the 21mer 5'-DCAGGCAGTTTCCTCTGGAAGG-3' (bases 312292 of the lower strand) derived from the sequence of exon 1 as primers. For detection of the codon 54 point mutation, 15 ml of this PCR product was digested with BanI. BanI cleaved the codon 54 wild-type allele into two fragments (245 and 84 bp) and left the allele with codon 54 mutation undigested. For detection of the codon 57 point mutation, 15 ml of the PCR product was digested with MboII. MboII cleaved the codon 57 mutated allele into two fragments (274 and 55 bp) and left the wild-type allele undigested. Point mutation at codon 52 was detected by amplification refractory mutation system-PCR as previously described [10]. DNA segment of the MBL gene, the oligonucleotides 5'-CTTCCCAGGCAAAGACGGGC-3' and 5'-CTTCCCAGGCAAAGACGGGT-3' were used as forward primers for the codon 52 wild-type and mutated allele, respectively (nucleotides 135154). Both forward primers contained an additional mis-match at the fifth nucleotide from the 3'-end to improve specificity. In both reactions, 5'-CAGGCAGTTTCCTCTGGAAGG-3' was used as reverse primer (nucleotides 244224). In homozygotes for the codon 52 wild-type allele, amplification only occurred with the MBL wild-type primer whereas in homozygotes for the codon 52 mutation, only with the primer that carried the mutation at the 3'-end, while heterozygotes showed amplification with both primers.
Statistics
All data were expressed as median and range unless otherwise specified. Statistical difference was analysed with
-square test and MannWhitney (nonparametric) test as appropriate. Two-way analysis of variance was used to investigate the differences in serum and peritoneal MBL level between study groups, adjusting for mutation and prior peritonitis. Serum and peritoneal MBL level were logarithmic transformed before analysis. Geometric means between study groups were compared in analysis of variance model. Tukey's method was used to adjust the P-values in multiple comparisons of study groups. Association between predictor variables and frequency of peritonitis was assessed by univariate and followed by multivariate multi-nominal logistic regression. All P-values quoted are two-tailed and the significance is defined as P<0.05.
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Results
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We recruited 199 patients from two regional dialysis centres for this study. Amongst 382 patients on long-term PD, 119 (31.2%) patients fulfilled the inclusion criteria and consented to the study. Sixty-eight (57.1%) and 52 (42.9%) patients were recruited as the FP and RP groups, respectively. They all received CAPD. Seventy-nine of our 97 haemodialysis patients (81.4%) consented to the study and 44 (55.7%) and 35 (44.3%) patients were recruited as the TF and HC groups, respectively. The demographic data of these patients are depicted in Table 1. The relevant dialysis information is summarized in Table 2. All patients in the FP group were using the twin-bag system while eight patients (15.4%) in the RP group used the spike system for CAPD treatment (P = 0.001). Amongst those 46 patients who were converted to HD after failing PD due to peritonitis, 18 (40.9%) used the spike system at the time of PD. The number of patients in the RP group with two or three and more than three episodes of peritonitis were 28 (53.8%) and 24 (46.2%), respectively. The causative organism and pattern of peritonitis in patients were Gram-positive, Gram-negative, mixed flora or culture negative.
MBL levels and gene mutation in PD patients
In our 120 patients on CAPD, 28 (23.3%) had codon 54 point mutation but none had 52 or 57 codon point mutation. Among those patients with mutation, only two were homozygous (serum MBL level, 178 and 231 ng/ml) and the remaining patients were heterozygous. The serum MBL level of PD patients with codon 54 point mutation (506 ng/ml, range: 1511458 ng/ml) was significantly lower than that of PD patients without mutation (2128 ng/ml, range: 4294903 ng/ml, P<0.0001) (Figure 1). Moreover, the MBL level in PD fluid from patients with codon 54 point mutation was also lower than that of PD patients without mutation (33.6 ng/ml, range: 24.185.3 ng/ml vs 44.6 ng/ml, range: 26.3165.2 ng/ml, P<0.001).

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Fig. 1. Serum MBL level in different groups of dialysis patients. FP, patients had no history of peritonitis (n = 168); RP, patients with repeated peritonitis (n = 52); TF, HD patients who previously developed technique failure due to peritonitis, (n = 44); HC, other HD patients (n = 35); PD, total patients on peritoneal dialysis (n = 120); HD, total patients on haemodialysis (n = 79); control, healthy subjects (n = 36). The horizontal bars represent median.
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The frequency of codon 54 mutation and the median level of serum MBL in different groups of patients are shown in Table 3. The codon 54 point mutation rate in the RP group (23.1%) was not different from that of the FP group (23.5%). There was no difference between the MBL level in PD fluid from patients with codon 54 mutation between the FP (34.7 ng/ml, range 24.748.9 ng/ml) and the RP group (32.6 ng/ml, range 24.185.3 ng/ml, P = 0.9). In sub-analysis, no difference in codon 54 mutation rate was demonstrated between FP and RP groups when patients on spike systems were excluded.
Relative risk factors of peritonitis on PD
On univariate analysis, the only risk factor associated with more than three peritonitis is age (P = 0.007) while the peritoneal MBL concentration did not suggest predictive value (P = 0.76) (Table 4). Table 5 summarizes independent risk factors predicting peritonitis in patients on long-term PD by multivariate analysis and again only age (OR 1.084, P = 0.004) is the significant risk factor.
MBL levels and gene mutation in HD patients
The median serum MBL level of the patients on HD was 1709 ng/ml (range, 2104794 ng/ml) (Figure 1). There were 15 patients (18.8%) with codon 54 point mutation but none had codon 52 or 57 point mutations. The median serum MBL level in patients with mutation was significantly lower than value in those without mutation (879 ng/ml, range 2101224 ng/ml vs 1958 ng/ml, range 4674794 ng/ml; P<0.001). Among HD patients with codon 54 point mutation, only two were homozygous (serum MBL level, 314 and 875 ng/ml). The codon point mutation rate and the MBL level did not differ between the TF and HC groups (Table 3).
Serum MBL level in dialysis patients with codon 54 point mutation
Although there was no significant difference of codon 54 point mutation rate among the different patient groups, there was significant difference in the serum MBL level in patients with code 54 point mutation with respect to mode of dialysis treatment (PD: 506 ng/ml, range 1511458 ng/ml vs HD: 879 ng/ml, range 2101224 ng/ml; P = 0.02). In contrast, there was no difference in the serum MBL level between PD patients and HD patients without mutation (2128 ng/ml, range 4294903 ng/ml vs 1958 ng/ml, range 4674794 ng/ml; P = 0.55). The correlation between the duration of dialysis and the serum MBL level was not significant (r = 0.052, P>0.05).
Two-way analysis of variance was used to compare the serum MBL level between different dialysis mode and study groups with the consideration for the effects of mutation and prior peritonitis on MBL level. We found no difference in PD MBL level between FP and RP groups [adjusted mean MBL (95%CI); FP 41.6 (37.446.2), RP 41.3 (36.047.3), P = 0.93]. Similarly, there was no difference in serum MBL level between TF and HC groups [adjusted mean MBL (95%CI); TF 1003.4 (799.01260.3), HC 1254.7 (1026.61533.4), P = 0.469]. Serum MBL between patients on PD and HD was not significantly different, after adjusting for the effect of mutation and prior peritonitis [adjusted mean MBL (95%CI); PD 946.2 (838.31067.8), HD 940.0 (721.11225.4), P = 0.97]. Serum MBL level of patients with prior peritonitis was not statistically different from those without prior peritonitis [adjusted mean MBL; with peritonitis 1006.7 (868.11167.4) and without peritonitis 883.5 (723.21079.4), P = 0.211].
Comparison of serum MBL level and gene mutation between healthy controls and dialysis patients
Of all 199 dialysis patients, the serum MBL level (1726 ng/ml, range 1514903 ng/ml) was significantly lower than that of healthy controls (2494 ng/ml, range 9079376 ng/ml, P = 0.004) despite the mutation rates were similar (21.6 vs 22.2%, P = 0.58). By two-way analysis of variance, the serum MBL level in healthy controls [mean MBL 1984.9 (1610.52446.4)] was higher than that of PD patients [mean MBL 833.7 (838.01049.5), P<0.001] and HD patients [mean MBL 1179.2 (1015.31369.4), P<0.001] after adjusting for the effect of mutation.
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Discussion
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PD-related peritonitis is the major morbidity and mortality factor in patients on maintenance PD treatment. Various strategies have been applied to decrease the infection especially in the area of connection of dialysis tubing. The development of closed systems such as the Ultra Y-set or the spike-less Ultra Twin bag has greatly reduced the incidence of peritonitis [11]. In our study, the patients in the FP group were all on a twin-bag system that may partly explain why they have a low risk of developing peritonitis when compared with the RP group. Prophylactic antibiotics for nasal carriers of S. aureus have also been shown to reduce peritonitis caused by S.aureus [12]. However, we do not routinely treat the nasal carriers unless they have exit site infection. Another important question is whether there are intrinsic factors in these patients that predispose to increased risk of infection.
MBL is an important component in the mammalian immune defence mechanism that helps to prevent infection. Patients with low serum MBL levels are associated with unusual and severe infections [8]. The serum level of MBL was mainly affected by liver function and the gene polymorphism. The level has not been found to be affected by the dialysis dose and other morbidity. In this study, we explored whether the serum MBL level or the MBL gene mutation may be associated with increased susceptibility to infection in patients on maintenance dialysis. We confirmed that both homozygous and heterozygous patients had a profoundly reduced serum level of MBL. In our patients on long-term renal replacement therapy (PD or HD), the codon 54 point mutation rate was comparable with healthy subjects in the same ethnic population [9]. In previous reports, the codon 54 point mutation occurs at a frequency of 0.23 yet codon 52 and 57 mutations are rarely detected in the Chinese population [9,13]. While an increased frequency of codon 54 point mutation is observed in Chinese patients with rheumatoid arthritis [14] or chronic hepatitis (hepatitis B and hepatitis C) [9], similar findings are not detected in our patients with end-stage renal failure on dialysis treatment.
Most intriguingly, despite a similar codon 54 point mutation rate in healthy subjects and dialysis patients, the latter group has a significantly lower serum level of MBL that is not simply related to mutation of the MBL gene. As the residual renal function contributed minimally to the clearance of MBL [15], we believe the low serum level of MBL in PD patients is probably due to loss via the peritoneal route and independent of the loss of renal function. The finding of a lower serum MBL level amongst dialysis patients is independent of the MBL gene mutation or the mode of dialysis treatment. Our finding raises the possibility that the MBL synthesis may be reduced by uraemia. Satomura et al. [16] reported a raised serum MBL level in HD and pre-HD patients, suggesting that elevated serum MBL altered the immune system and accelerated atherogenesis. In that study, no MBL gene mutation was studied and no explanation was offered for the paradoxical finding of proneness to the development of infectious complications with a raised serum MBL level. Our data represent a more accurate MBL level of patients with end-stage renal disease as gene mutation has been investigated. It is well recognized that patients with end-stage renal disease treated by dialysis have higher annual mortality rates caused by sepsis compared with the general population, even after stratification for age, race and DM [17]. Our findings of a lower serum MBL level in dialysis patients (PD or HD) independent of MBL gene mutation may be one of the underlying factors that contribute to the increased risk of sepsis in the dialysis population.
The other interesting issue is whether a lower serum and peritoneal MBL level predisposes PD patients to the risk of peritonitis. We used two-way analysis of variance to compare the serum MBL level between different dialysis modes and study groups in order to adjust for the effect of mutation on MBL level. We also used the same method to compare the peritoneal MBL between study groups in the same dialysis mode. We found no difference in the serum and peritoneal MBL level or frequency of codon 54 point mutation between PD patients with repeated peritonitis and those without peritonitis. There was no difference in the serum MBL level between the RP group and those PD patients requiring transfer to HD due to previous severe peritonitis (TF) or patients on chronic HD (HC). Although one may argue that some patients with low serum MBL level might have died of severe peritonitis and hence were not recruited into this study, the possibility is low as the mortality rate for peritonitis is not high in our centres. Peritonitis or severe sepsis as the direct cause of death occurred in 28 of 209 PD patients (13.3%) over a 12 year period in our centres [18].
The lack of obvious correlation between peritonitis and serum MBL level does not necessarily rule out the importance of MBL in defence immunity in PD. The existence of other predisposing risk factors including connection technique, nasal S.aureus carriers, bowel pathology and personal hygiene will preclude the MBL level as the single primary factor for peritonitis in PD patients. However, it is interesting to note that PD patients with codon 54 point mutation have a lower serum MBL level compared with HD patients with similar MBL gene mutation. The underlying mechanism for the difference is not known. We speculate that the peritoneal clearance of MBL may contribute to some of the observed difference. The median peritoneal clearance of MBL is 0.15 ml/min (range 0.052.77 ml/min) in our PD patients. The continuous loss of MBL via the peritoneal clearance may contribute to the low serum MBL level especially in those patients with an intrinsically lower serum MBL level due to MBL gene mutation. McGregor et al. [19] demonstrated that the immunoglobulin G (IgG), complement 3 (C3) and transferrin concentrations in PD effluent of patients on CAPD were 12% of those in serum and these values were much lower than those in normal peritoneal fluid. They also found a negative correlation between frequency of peritonitis and the opsonic activity of PD effluent, which was plausibly determined by the levels of IgG and C3 in peritoneal cavity [19]. However, other investigators did not find a lower peritoneal concentration of IgG and C3 in patients with frequent peritonitis [20]. Peritoneal host defence and dialysis connectology are the important determinants for PD-related peritonitis. The role played by other cytokines, complements and toll-like receptor in the PD-related peritonitis warrants further investigation.
In conclusion, our dialysis patients have a lower serum MBL level than a healthy control group despite a comparable codon 54 point mutation rate. This may be another intrinsic factor for altered immune defence mechanism in uraemic patients. Patients on PD with repeated peritonitis are not associated with a higher incidence of MBL gene mutations. The existence of other predisposing risk factors such as connection technique, nasal S.aureus carriers, bowel pathology and personal hygiene precludes the MBL level as the single primary factor for peritonitis in PD patients.
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Acknowledgments
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This research was supported by a grant from the Department of Medicine, University of Hong Kong. J.C.K.L. was supported by L & T Charitable Foundation and INDOCAFE. We thank the nursing staff at the dialysis units of the Queen Mary and Tung Wah Hospitals for their assistance.
Conflict of interest statement. None declared.
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Received for publication: 5. 7.05
Accepted in revised form: 27. 7.05