Low Pretransplantation Mannose-Binding Lectin Levels Predict Superior Patient and Graft Survival after Simultaneous Pancreas-Kidney Transplantation
Stefan P. Berger*,
Anja Roos*,,
Marko J.K. Mallat*,
Alexander F.M. Schaapherder,
Ilias I. Doxiadis,
Cees van Kooten*,
Friedo W. Dekker||,
Mohamed R. Daha* and
Johan W. de Fijter*
Departments of * Nephrology, Clinical Chemistry, Surgery, Immunohematology and Bloodtransfusion, and || Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands
Correspondence: Dr. Stefan P. Berger, Department of Nephrology, C3-P25, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, Netherlands. Phone: +31-71-526-2148; Fax: +31-71-526-6868; s.p.berger{at}lumc.nl
Received for publication March 2, 2007.
Accepted for publication May 2, 2007.
Simultaneous pancreas-kidney transplantation (SPKT) is the treatmentof choice for patients with type 1 diabetes and renal failure.However, this procedure is characterized by a high rate of postoperativeinfections, acute rejection episodes, and cardiovascular mortality.The lectin pathway of complement activation contributes to cardiovasculardisease in diabetes and may play an important role in inflammatorydamage after organ transplantation. This study therefore soughtto determine how mannose-binding lectin (MBL), a major recognitionmolecule of the lectin pathway of complement activation, influencesoutcome after SPKT. MBL serum levels were determined in 99 andMBL genotypes in 97 consecutive patients who received an SPKTfrom 1990 through 2000 and related to patient and graft survival.At 12 yr, cumulative death-censored kidney graft survival was87.5% in patients with an MBL level <400 ng/ml and 74.8%in the group with MBL levels >400 ng/ml (P = 0.021). Pancreasgraft survival was significantly better in patients with lowMBL levels (P = 0.016). MBL levels >400 ng/ml were associatedwith a hazard ratio of 6.28 for patient death (95% confidenceinterval 1.8 to 20.3; P = 0.003). Accordingly, survival wassignificantly better in recipients with MBL gene polymorphismsassociated with low MBL levels. These findings identify MBLas a potential risk factor for graft and patient survival inSPKT. It is hypothesized that MBL contributes to the pathogenesisof inflammation-induced vascular damage both in the transplantedorgans and in the recipient's native blood vessels.
Simultaneous pancreas-kidney transplantation (SPKT) is the preferredtreatment option for patients with long standing type 1 diabetesand end-stage renal failure. The major arguments favoring SPKTin these patients rather than renal transplantation alone includeimproved quality of life, prevention of recurrent diabetic nephropathy,and stabilization of diabetic neuropathy and retinopathy. Recentstudies demonstrated that SPKT, compared with kidney transplantationalone, leads to improved allograft survival1 and improved patientsurvival.2,3 Despite these benefits, mortality after SPKT transplantationremains high, with 10-yr patient survival rates of <70%.2,4
The complement system contributes to tissue damage at variousstages of the transplantation process. An important role inischemia/reperfusion injury and acute rejection has been demonstratedin various animal models.5,6 Recently, the F/F and F/S donorallotypes of the C3 complement molecule have been associatedwith better long-term outcome after kidney transplantation.7
Mannose-binding lectin (MBL) is the major recognition moleculeof the lectin pathway of complement activation. In host defense,wild-type MBL binds to carbohydrate moieties, leading to complementdeposition, opsonization, and elimination of pathogens. Single-nucleotidepolymorphisms (SNP) in the structural as well as regulatoryparts of the MBL gene lead to large interindividual variationsin the concentration of functional MBL in serum.8
Various studies showed an association of low serum MBL levelsand MBL SNP with decreased host defense against various infectiousagents. This is especially apparent in situations of impairedadaptive immunity, such as early childhood or prolonged immunosuppression.9–12However, wild-type MBL may also interact with tissue and leadto complement-mediated enhancement of damage in various noninfectiousinflammatory settings. In ischemia/reperfusion damage, MBL maycontribute to tissue injury by binding to host cells exhibitinga modified surface.13,14 Recently, high MBL levels were relatedto an increased risk for vascular disease and diabetic nephropathyin both patients with type 1 and type 2 diabetes.15–17
Our group has shown that low pretransplantation MBL levels areassociated with better graft survival after deceased-donor kidneytransplantation.18 In view of the role of MBL in diabetes andtransplantation, we hypothesized that MBL could be a major determinantof outcome in SPKT, which is characterized by a high rate ofinfectious complications, acute graft rejection, and cardiovascularmortality.
The mean MBL concentration in the 99 available sera obtaineddirectly before transplantation was 1053 ng/L. The median concentrationwas 694 ng/ml. A cutoff of 400 ng/ml was used to discriminatebetween high and low MBL levels. This cutoff correlates withthe presence of SNP in the first exon of the MBL gene in botha control population19 and the recipients studied here (Figure 1).The median MBL concentration in SPKT recipients with only wild-typeMBL alleles (A/A) was 1493 ng/ml (n = 54). In recipients withthe A/O (n = 29) or O/O (n = 4) genotype, the median MBL concentrationswere 245 and 166 ng/ml, respectively. Of the patients with anMBL level >400 ng/ml, 89.3% had only wild-type MBL alleles(A/A), whereas 90% of the patients with an MBL level <400ng/ml had at least one of the exon 1 MBL polymorphisms (A/Oor O/O). To assess whether pretransplantation MBL levels arerepresentative of the levels after transplantation, we determinedthe MBL concentrations 1 yr after SPKT in 30 patients and comparedthem with the levels measured in the pretransplantation sample.We found a high intraindividual correlation of MBL levels overtime (r = 0.87, P < 0.0001).
Figure 1. Pretransplantation mannose-binding lectin (MBL) levels stratified according to MBL genotype. The dashed line represents the cutoff level of 400 ng/ml. MBL levels are represented on a log scale.
Thirty-four (34.3%) SPKT recipients had a low MBL level, and65 (65.6%) recipients had a high MBL level. Table 1 shows thecharacteristics of the high and low MBL recipients. No significantdifference between both groups concerning demographic and clinicalcharacteristics including donor and recipient age, cytomegalovirusstatus, and gender distribution was noted. Both groups had acomparable proportion of patients undergoing SPKT before initiationof dialysis treatment. Both the high- and low-MBL groups hada comparable proportion of patients receiving triple immunosuppressionincluding mycophenolate mofetil. The proportion of patientswith at least one significant coronary stenosis was 27.3% inthe low-MBL group and 22.3% in the high-MBL group (P = 0.58).Of note, there was no difference in the baseline C-reactiveprotein (CRP) levels between the two MBL groups. The majorityof patients required treatment for acute rejection, 88.2 and86.2% in the low- and high-MBL groups, respectively (P = 0.99).Likewise, the number of rejection treatments per patient wascomparable in both groups (1.85 versus 1.68; P = 0.49).
Table 1. Characteristics of study population according to MBL levelsa
Analysis for death-censored graft survival revealed a significantsurvival advantage for both the renal and the pancreas allograftsin favor of the low-MBL recipients. At 12 yr after transplantation,cumulative death-censored pancreas graft survival was 100% inthe low-MBL group versus 82% in the high-MBL group (P = 0.016by the log-rank test with grafts lost within 1 wk excluded;Figure 2A). Death-censored renal allograft survival at 12 yrafter transplantation was 87.5% in patients with an MBL level<400 ng/ml and 74.8% in patients with an MBL level >400ng/ml (P = 0.021 by the log-rank test; Figure 2B).
Figure 2. Unadjusted Kaplan-Meier survival curves according to pretransplantation MBL level. (A) Death-censored survival of pancreas allografts. (B) Death-censored survival of kidney allografts.
Subsequently, the MBL status was related to patient survival.Twelve years after transplantation, cumulative patient survivalwas 86.9% in the low-MBL group and 49.1% in the high-MBL group(P = 0.001 by the log rank test; Figure 3A). To examine whetherthe inferior patient survival in high-MBL recipients was a mereconsequence of graft loss, we repeated the survival analysisafter excluding the patients who lost either the kidney or thepancreas allograft. In the group with functioning allografts,patient survival remained inferior in those with MBL levels>400 ng/ml (P = 0.02).
Figure 3. Unadjusted Kaplan-Meier survival curves of patient survival according to MBL status. (A) Patient survival according to pretransplantation MBL level. (B) Patient survival according to recipient MBL genotype. A/A, wild-type MBL genotype; A/O or O/O, variant MBL genotype.
To confirm these findings, we also analyzed recipient survivalaccording to the MBL genotype. Superior survival was found inpatients with a variant MBL genotype when compared with recipientswith only wild-type MBL alleles (P = 0.026; Figure 3B).
We analyzed various characteristics in relation to patient survival(Table 2). An MBL level >400 ng/ml was associated with astrongly increased mortality (hazard ratio 6.28; 95% confidenceinterval 1.89 to 20.87; P = 0.003). Accordingly, the presenceof wild-type MBL alleles was associated with an increased riskfor patient death (hazard ratio 3.6; 95% confidence interval1.22 to 10.6; P = 0.02). MBL was also significantly associatedwith an increased risk for patient death when analyzed as acontinuous parameter (P = 0.013). MBL remained significantlyassociated with patient death when entered into a multivariatemodel adjusted for recipient age, gender, and baseline CRP usingthe Cox regression method (Table 2).
The reasons for patient death in the high- and low-MBL groupsare shown in Table 3. The excess mortality in patients withan MBL level >400 ng/ml was explained to a large extent bya higher cardiovascular mortality in this group. No significantdifference in infection-related deaths between the low- andhigh-MBL groups was observed.
Our study demonstrates superior graft and patient survival afterSPKT in recipients with low MBL levels. A high MBL level wasassociated with an increased incidence of death-censored lossof both the renal and the pancreatic allograft. Furthermore,a high-MBL status was associated with markedly increased mortality,and we demonstrate that this high-MBL status is geneticallydetermined.
These findings corroborate our recent report demonstrating anassociation of MBL levels >400 ng/ml with poorer graft survivalafter deceased-donor kidney transplantation.18 Our earlier studyon the role of MBL in kidney transplantation showed a nonsignificanttrend toward poorer patient survival in renal allograft recipientswith a high MBL level. This difference between the two studiesmay be explained by the higher risk profile in the patientswho had type 1 diabetes and received SPKT compared with thegeneral population of kidney allograft recipients. In addition,the harmful effect of MBL in cardiovascular mortality may beenhanced in the patients with diabetes.
Reports on the cardiovascular effects of MBL deficiency in thegeneral population have been inconclusive. The predictive valueof MBL levels for myocardial infarction was studied in the population-basedReykjavik study.20 In this population, MBL levels >1000 ng/mlwere associated with a lower odds ratio for myocardial infarction.It is interesting that no data on mortality were reported. Inthe Strong Heart Study cohort, Native Americans with coronaryheart disease had an increased frequency of variant MBL genotypeswhen compared with a matched cohort without coronary heart disease.21Contrary to these findings but in agreement with our data inthis study, a recent study in 964 seemingly healthy men didshow an association of elevated MBL levels with coronary heartdisease.22
So how can we explain the adverse effect of high MBL levelson graft and patient survival in our study? The finding of superiorgraft survival after SKPT confirms our earlier report demonstratingsuperior allograft survival in recipients with low MBL levelsafter deceased-donor renal transplantation.18 As in our SPKTcohort, the incidence of acute rejection was similar in thehigh- and low-MBL groups, but graft loss as a result of rejectionoccurred much more frequently in recipients with high MBL levels.We hypothesize that MBL contributes to tissue damage in variousinflammatory settings, including graft rejection. Models ofischemia/reperfusion damage in heart, intestine, and kidneyhave shown that MBL A and C–deficient mice are protectedfrom ischemia/reperfusion injury as compared with wild-typemice.13,23,24 In line with these findings, MBL deposition wasdetected in human kidneys with ischemia/reperfusion damage,25indicating that wild-type MBL may contribute to local complementactivation and enhanced inflammation in tissue damage. Nextto the interaction of MBL with apoptotic and necrotic cells,26MBL-mediated damage may also be related to its antibody-bindingcapacities.27–29 A recent study failed to show an associationbetween MBL levels and patient or graft survival after kidneytransplantation.30 In comparison with our studies, it has tobe noted that the analysis was performed using the median MBLlevel or the third quartile as cutoff values, which may notbe ideal for detecting MBL-mediated effects.
In addition to the effect of MBL on graft survival, we observeda strong association of high MBL levels with inferior patientsurvival that was independent of graft survival. Earlier studiespointed toward a detrimental role of MBL in patients with diabetes.High levels of MBL have been associated with an increased frequencyof cardiovascular disease and proteinuria in patients with type1 diabetes.15,16 Similarly, high MBL levels have been relatedto increased mortality in patients with type 2 diabetes.17 Itmay well be that MBL exerts a specific harmful effect in thediabetic milieu and the increased mortality in high-MBL patientsmay be related to microvascular damage obtained before the pancreastransplantation. In addition, the unfavorable effect of MBLobserved in the context of ischemia/reperfusion damage may contributeto tissue damage and mortality after cardiovascular events.
Because intraindividual MBL levels are highly stable over time,20we are convinced that serum MBL levels measured before transplantationadequately represent the exposition to MBL. Moreover, our MBLassay strongly correlates with both the functional activityof the lectin pathway19 and the presence of SNP of the MBL gene.In fact, measurement of MBL levels in serum may be a more powerfuland convenient method of detecting MBL-mediated effects thangenotyping, because not all intraindividual variations in MBLlevels are explained by the known polymorphisms of exon 1 andother parts of the MBL gene.
Recently, low MBL levels were related to an increased incidenceof clinically important infections after liver transplantation.12However, no association between MBL deficiency and infection-relatedmortality was detected in our cohort. Low infection-relatedmortality after SPKT has been reported before.31 Thus, althoughwe cannot exclude that MBL deficiency is associated with anincreased incidence of infections after SPKT, this did not contributeto graft survival or patient mortality in our cohort.
MBL levels are a powerful predictor of graft and patient survivalafter SPKT. If these findings can be confirmed in other studypopulations, then determination of MBL levels and/or MBL genotypingmay aid risk stratification before SPKT. Whether these findingseventually lead to new therapeutic approaches will depend onthe elucidation of the underlying pathophysiologic mechanisms.
Study Population
Between January 1990 and December 2000, 114 SPKT were performedin the Leiden University Medical Center. All patients had type1 diabetes. Pretransplantation serum was available from 99 andDNA from 97 of these consecutive recipients. Both pretransplantationserum and DNA were available from 87 of these patients. Pretransplantationsera were routinely obtained at the time of admission for transplantationand stored in aliquots at –80°C. All measurementsof MBL were performed in sera that had been frozen and thawedonly once. All included patients were regularly followed atour center. None of the 99 patients was lost to follow up. Thestudy was performed according to the guidelines of the ethicscommittee of the Leiden University Medical Center, and patientanonymity was maintained.
The following clinical data were collected using the LeidenTransplant Database: Donor variables, including gender and ageat time point of death; recipient variables (age at time oftransplantation, gender, panel-reactive antibodies, cytomegalovirusstatus, duration of diabetes and dialysis treatment, smokingstatus, and cholesterol levels); transplantation-related factors(HLA-A, -B, and -DR mismatches; cold ischemia time); and posttransplantationfeatures, including immunosuppressive regimen, occurrence ofdelayed graft function, acute rejection history, rejection treatment,status of both the kidney and the pancreas allografts, causeof allograft loss, vital status, and cause of death. Rejectionwas defined as either biopsy-proven rejection or clinical rejectionof the kidney with a favorable response to antirejection treatment.Because pancreas rejection is difficult to diagnose and isolatedrejection of the pancreas is a rare event, this was not analyzedseparately in this study. After transplantation, patients werefollowed until death or until January 1, 2006. Until May 1995,standard maintenance immunosuppression consisted of prednisone,cyclosporine, and azathioprine. All recipients who receiveda transplant after May 1995 received prednisolone, cyclosporine,and mycophenolate mofetil. Eighteen patients received inductiontreatment with OKT-3 between 1991 and 1994. From 1999 onward,induction treatment was reinitiated and consisted of eitherpolyclonal antithymocyte globulin (Fresenius, Bad Homburg, Germany)or daclizumab (n = 19). Acute rejection episodes were treatedaccording to a standard protocol consisting of methylprednisolone1 g intravenously for 3 consecutive days; a 10-d course of antithymocyteglobulin at a dosage of 5 mg/kg guided by absolute lymphocytecounts; or again methylprednisolone for the first, second (orsteroid-resistant), or third rejection episode, respectively.
ELISA
Serum MBL levels were assessed by sandwich ELISA as describedpreviously.18 In brief, 96-well ELISA plates (Greiner, Frickenhausen,Germany) were coated with the mAb 3E7 (mouse IgG1 anti-MBL at2.5 µg/ml; provided by Dr. T. Fujita, Fuhushima, Japan).Serum samples were diluted 1:50 and 1:500 and incubated in thecoated wells. MBL was detected with Dig-conjugated 3E7. Detectionof binding of Dig-conjugated antibodies was performed usinghorseradish peroxidase–conjugated sheep anti-Dig antibodies(Fab fragments; Roche, Mannheim, Germany). Enzyme activity wasdetected using 2,2'-azino-bis(3-ethybenzthiazoline-6-sufonicacid) (Sigma Chemical Co., St. Louis, MO). The optical densitywas measured at 415 nm using a microplate biokinetics reader(EL312e; Biotek Instruments, Winooski, VT). A calibration linewas produced using human serum from a healthy donor with a knownconcentration of MBL. Earlier studies indicated that this assayprimarily detects wild-type MBL in serum and plasma and thatthere is a direct association with the MBL genotype and withMBL function.19
Genotyping
DNA from 97 SPKT recipients was isolated routinely from blood.MBL SNP at codons 52, 54, and 57 of the mbl2 gene were typedby high-resolution DNA melting analysis.32 The detailed methodwill be published separately (A.R. et al., manuscript in preparation).The MBL genotype of only wild-type allele carriers is designatedas A/A, and the presence of one or two variant alleles (B, C,or D) is designated as A/O or O/O. In the survival analysis,carriers of A/O and O/O MBL genotype were considered as onegroup.
Statistical Analyses
Categorical characteristics were compared using cross-tableswith calculation of the exact P values. Interval variables wereanalyzed using the independent-samples t test when assumptionsfor parametric testing were met. Otherwise, the Mann-WhitneyU test was used. Patient and graft survival was estimated usingthe Kaplan-Meier product-limit method, and the curves were comparedwith the log-rank test. For both pancreas and renal allograftsurvival, the analysis was censored for patient death. Organsthat were lost as a result of technical failure or thrombosiswithin 1 wk after transplantation were excluded from survivalanalysis.
Cox proportional hazards regression was used to identify possibleconfounders influencing baseline MBL levels. In the multivariatemodel, MBL was adjusted for recipient age, gender, and baselineCRP level. MBL was tested both as a dichotomous (MBL < or>400 ng/ml) and as a continuous factor (after log transformation).P < 0.05 was considered to be significant. Data analysiswas performed with SPSS Statistical Software Package (version11.0.1; SPSS, Chicago, IL).
This study was supported in part by the Dutch Kidney Foundation(grant CO3-694).
We thank Prof. Teizo Fujita (Fuhushima, Japan) for providingthe anti-MBL antibody (3E7). We also acknowledge the excellenttechnical assistance by Nicole Schlagwein and Reinier van derGeest and thank Rolf H. Vossen (Department of Genetics, LeidenUniversity Mediacl Center) for help with the genotyping.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
Israni AK, Feldman HI, Propert KJ, Leonard M, Mange KC: Impact of simultaneous kidney-pancreas transplant and timing of transplant on kidney allograft survival.
Am J Transplant 5
: 374
–382, 2005[CrossRef][Medline]
Ojo AO, Meier-Kriesche HU, Hanson JA, Leichtman A, Magee JC, Cibrik D, Wolfe RA, Port FK, Agodoa L, Kaufman DB, Kaplan B: The impact of simultaneous pancreas-kidney transplantation on long-term patient survival.
Transplantation 71
: 82
–90, 2001[CrossRef][Medline]
Smets YF, Westendorp RG, van der Pijl JW, de Charro FT, Ringers J, de Fijter JW, Lemkes HH: Effect of simultaneous pancreas-kidney transplantation on mortality of patients with type-1 diabetes mellitus and end-stage renal failure.
Lancet 353
: 1915
–1919, 1999[CrossRef][Medline]
Pruijm MT, de Fijter HJ, Doxiadis II, Vandenbroucke JP: Preemptive versus non-preemptive simultaneous pancreas-kidney transplantation: A single-center, long-term, follow-up study.
Transplantation 81
: 1119
–1124, 2006[CrossRef][Medline]
Zhou W, Farrar CA, Abe K, Pratt JR, Marsh JE, Wang Y, Stahl GL, Sacks SH: Predominant role for C5b-9 in renal ischemia/reperfusion injury.
J Clin Invest 105
: 1363
–1371, 2000[Medline]
Pratt JR, Basheer SA, Sacks SH: Local synthesis of complement component C3 regulates acute renal transplant rejection.
Nat Med 8
: 582
–587, 2002[CrossRef][Medline]
Brown KM, Kondeatis E, Vaughan RW, Kon SP, Farmer CK, Taylor JD, He X, Johnston A, Horsfield C, Janssen BJ, Gros P, Zhou W, Sacks SH, Sheerin NS: Influence of donor C3 allotype on late renal-transplantation outcome.
N Engl J Med 354
: 2014
–2023, 2006[Abstract/Free Full Text]
Garred P, Pressler T, Lanng S, Madsen HO, Moser C, Laursen I, Balstrup F, Koch C, Koch C: Mannose-binding lectin (MBL) therapy in an MBL-deficient patient with severe cystic fibrosis lung disease.
Pediatr Pulmonol 33
: 201
–207, 2002[CrossRef][Medline]
Mullighan CG, Heatley S, Doherty K, Szabo F, Grigg A, Hughes TP, Schwarer AP, Szer J, Tait BD, Bik TL, Bardy PG: Mannose-binding lectin gene polymorphisms are associated with major infection following allogeneic hemopoietic stem cell transplantation.
Blood 99
: 3524
–3529, 2002[Abstract/Free Full Text]
Koch A, Melbye M, Sorensen P, Homoe P, Madsen HO, Molbak K, Hansen CH, Andersen LH, Hahn GW, Garred P: Acute respiratory tract infections and mannose-binding lectin insufficiency during early childhood.
JAMA 285
: 1316
–1321, 2001[Abstract/Free Full Text]
Bouwman LH, Roos A, Terpstra OT, de Knijff P, van Hoek B, Verspaget HW, Berger SP, Daha MR, Frolich M, van der Slik AR, Doxiadis II, Roep BO, Schaapherder AF: Mannose binding lectin gene polymorphisms confer a major risk for severe infections after liver transplantation.
Gastroenterology 129
: 408
–414, 2005[CrossRef][Medline]
Moller-Kristensen M, Wang W, Ruseva M, Thiel S, Nielsen S, Takahashi K, Shi L, Ezekowitz A, Jensenius JC, Gadjeva M: Mannan-binding lectin recognizes structures on ischaemic reperfused mouse kidneys and is implicated in tissue injury.
Scand J Immunol 61
: 426
–434, 2005[CrossRef][Medline]
Walsh MC, Bourcier T, Takahashi K, Shi L, Busche MN, Rother RP, Solomon SD, Ezekowitz RA, Stahl GL: Mannose-binding lectin is a regulator of inflammation that accompanies myocardial ischemia and reperfusion injury.
J Immunol 175
: 541
–546, 2005[Abstract/Free Full Text]
Hansen TK, Tarnow L, Thiel S, Steffensen R, Stehouwer CD, Schalkwijk CG, Parving HH, Flyvbjerg A: Association between mannose-binding lectin and vascular complications in type 1 diabetes.
Diabetes 53
: 1570
–1576, 2004[Abstract/Free Full Text]
Hovind P, Hansen TK, Tarnow L, Thiel S, Steffensen R, Flyvbjerg A, Parving HH: Mannose-binding lectin as a predictor of microalbuminuria in type 1 diabetes: An inception cohort study.
Diabetes 54
: 1523
–1527, 2005[Abstract/Free Full Text]
Hansen TK, Gall MA, Tarnow L, Thiel S, Stehouwer CD, Schalkwijk CG, Parving HH, Flyvbjerg A: Mannose-binding lectin and mortality in type 2 diabetes.
Arch Intern Med 166
: 2007
–2013, 2006[Abstract/Free Full Text]
Berger SP, Roos A, Mallat MJ, Fujita T, de Fijter JW, Daha MR: Association between mannose-binding lectin levels and graft survival in kidney transplantation.
Am J Transplant 5
: 1361
–1366, 2005[CrossRef][Medline]
Roos A, Garred P, Wildenberg ME, Lynch NJ, Munoz JR, Zuiverloon TC, Bouwman LH, Schlagwein N, Van Den Houten FC, Faber-Krol MC, Madsen HO, Schwaeble WJ, Matsushita M, Fujita T, Daha MR: Antibody-mediated activation of the classical pathway of complement may compensate for mannose-binding lectin deficiency.
Eur J Immunol 34
: 2589
–2598, 2004[CrossRef][Medline]
Saevarsdottir S, Oskarsson OO, Aspelund T, Eiriksdottir G, Vikingsdottir T, Gudnason V, Valdimarsson H: Mannan binding lectin as an adjunct to risk assessment for myocardial infarction in individuals with enhanced risk.
J Exp Med 201
: 117
–125, 2005[Abstract/Free Full Text]
Best LG, Davidson M, North KE, MacCluer JW, Zhang Y, Lee ET, Howard BV, DeCroo S, Ferrell RE: Prospective analysis of mannose-binding lectin genotypes and coronary artery disease in American Indians: The Strong Heart Study.
Circulation 109
: 471
–475, 2004[Abstract/Free Full Text]
Keller TT, van Leuven SI, Meuwese MC, Wareham NJ, Luben R, Stroes ES, Hack CE, Levi M, Khaw KT, Boekholdt SM: Serum levels of mannose-binding lectin and the risk of future coronary artery disease in apparently healthy men and women.
Arterioscler Thromb Vasc Biol 26
: 2345
–2350, 2006[CrossRef][Medline]
Hart ML, Ceonzo KA, Shaffer LA, Takahashi K, Rother RP, Reenstra WR, Buras JA, Stahl GL: Gastrointestinal ischemia-reperfusion injury is lectin complement pathway dependent without involving C1q.
J Immunol 174
: 6373
–6380, 2005[Abstract/Free Full Text]
Jordan JE, Montalto MC, Stahl GL: Inhibition of mannose-binding lectin reduces postischemic myocardial reperfusion injury.
Circulation 104
: 1413
–1418, 2001[Abstract/Free Full Text]
de Vries B, Walter SJ, Peutz-Kootstra CJ, Wolfs TG, van Heurn LW, Buurman WA: The mannose-binding lectin-pathway is involved in complement activation in the course of renal ischemia-reperfusion injury.
Am J Pathol 165
: 1677
–1688, 2004[Abstract/Free Full Text]
Nauta AJ, Raaschou-Jensen N, Roos A, Daha MR, Madsen HO, Borrias-Essers MC, Ryder LP, Koch C, Garred P: Mannose-binding lectin engagement with late apoptotic and necrotic cells.
Eur J Immunol 33
: 2853
–2863, 2003[CrossRef][Medline]
Roos A, Bouwman LH, Gijlswijk-Janssen DJ, Faber-Krol MC, Stahl GL, Daha MR: Human IgA activates the complement system via the mannan-binding lectin pathway.
J Immunol 167
: 2861
–2868, 2001[Abstract/Free Full Text]
Roos A, Rastaldi MP, Calvaresi N, Oortwijn BD, Schlagwein N, Gijlswijk-Janssen DJ, Stahl GL, Matsushita M, Fujita T, van Kooten C, Daha MR: Glomerular activation of the lectin pathway of complement in IgA nephropathy is associated with more severe renal disease.
J Am Soc Nephrol 17
: 1724
–1734, 2006[Abstract/Free Full Text]
Arnold JN, Wormald MR, Suter DM, Radcliffe CM, Harvey DJ, Dwek RA, Rudd PM, Sim RB: Human serum IgM glycosylation: Identification of glycoforms that can bind to mannan-binding lectin.
J Biol Chem 280
: 29080
–29087, 2005[Abstract/Free Full Text]
Hjelmesaeth J, Ueland T, Flyvbjerg A, Bollerslev J, Leivestad T, Jenssen T, Hansen TK, Thiel S, Sagedal S, Roislien J, Hartmann A: Early posttransplant serum osteoprotegerin levels predict long-term (8-year) patient survival and cardiovascular death in renal transplant patients.
J Am Soc Nephrol 17
: 1746
–1754, 2006[Abstract/Free Full Text]
Smets YF, van der Pijl JW, van Dissel JT, Ringers J, de Fijter JW, Lemkes HH: Infectious disease complications of simultaneous pancreas kidney transplantation.
Nephrol Dial Transplant 12
: 764
–771, 1997[Abstract/Free Full Text]
Zhou L, Wang L, Palais R, Pryor R, Wittwer CT: High-resolution DNA melting analysis for simultaneous mutation scanning and genotyping in solution.
Clin Chem 51
: 1770
–1777, 2005[Abstract/Free Full Text]
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Abstract
Introduction
