Apolipoprotein A-IV Serum Concentrations Are Elevated in Patients with Mild and Moderate Renal Failure
Florian Kronenberg*,
Erich Kuen*,
Eberhard Ritz,
Paul König,
Günter Kraatz¶,
Karl Lhotta,
Johannes F. E. Mann,
Gerhard A. Müller||,
Ulrich Neyer#,
Werner Riegel**,
Peter Riegler,
Vedat Schwenger and
Arnold von Eckardstein¶¶
*Institute of Medical Biology and Human Genetics, University of Innsbruck, Innsbruck, Austria; Department of Internal Medicine, Division of Nephrology, Ruperto-Carola-University, Heidelberg, Germany; Innsbruck University Hospital, Department of Clinical Nephrology, Austria; ¶Department of Internal Medicine A, Ernst-Moritz-Arndt-University Greifswald, Germany; München Schwabing Hospital, LMU, Munich, Germany; ||Department of Nephrology and Rheumatology, Georg-August-University, Göttingen, Germany; #Feldkirch Hospital, Department of Nephrology and Dialysis Feldkirch, Austria; **Medizinische Universitätskliniken des Saarlandes, Innere Medizin IV, Homburg/Saar, Germany; Bozen Hospital, Division of Nephrology and Hemodialysis, Bozen, Italy; and ¶¶Institute of Clinical Chemistry and Laboratory Medicine and Institute of Arteriosclerosis Research, University of Münster, Germany.
Correspondence to Dr. Florian Kronenberg, Institute of Medical Biology and Human Genetics, University of Innsbruck, Schöpfstrasse 41, A-6020 Innsbruck, Austria. Phone: Phone: +43 512 507 3474; Fax: +43 512 507 2861; E-mail: Florian.Kronenberg{at}uibk.ac.at
ABSTRACT. Cell culture studies and investigations in mice thatoverexpress either human or mouse apolipoprotein A-IV (apoA-IV)revealed anti-atherogenic properties of apoA-IV. An associationbetween low apoA-IV concentrations and coronary artery diseasein humans was demonstrated; therefore, apoA-IV may also playan antiatherogenic role in humans. Because apoA-IV is markedlyelevated in dialysis patients, patients with the earliest andmodest stages of renal impairment were studied to assess theassociation of apoA-IV with GFR and atherosclerotic complications.GFR was measured by the use of iohexol in 227 non-nephroticpatients with different degrees of renal impairment. ApoA-IVincreased significantly with decreasing GFR and was alreadyelevated in earliest stages of renal disease (GFR > 90 ml/minper 1.73 m2). Multiple linear regression analysis identifiedrenal function parameters (GFR, creatinine, and urea) as themost important determinants of apoA-IV levels in serum of thesepatients. Twenty-six patients had already experienced 36 atheroscleroticevents. Logistic regression analysis identified three variablesassociated with atherosclerotic complications: age, apoA-IV,and gender. Each 1 mg/dl increase of apoA-IV decreased the oddsratio for an atherosclerotic complication by 8% (P = 0.011).The data clearly show that the anti-atherogenic apoA-IV startsto increase during the earliest phases of renal insufficiency,which makes apoA-IV an early marker of renal impairment.
The glycoprotein apolipoprotein A-IV (apoA-IV) is almost exclusivelyproduced in intestinal human enterocytes and secreted into thelymph (1). It is a structural protein of chylomicrons; the meanplasma levels are approximately 15 mg/dl (2). In the fastingstate, the majority of apoA-IV circulates in plasma as partof a lipid-poor, small HDL-like particle that does not containapoA-I (3,4).
The physiologic function of apoA-IV is controversial. It waspostulated to be involved in fat absorption (5) and regulationof food intake (6), but both findings were not confirmed ingenetically modified mice (7,8). In vitro studies reported convincingevidence that apoA-IV participates in several steps of the reversecholesterol transport pathway, which removes cholesterol fromperipheral cells and directs it to liver and steroidogenic organsfor metabolization (9–11). ApoA-IV activates lecithin:cholesterolacyltransferase (12,13) and modulates the activation of lipoproteinlipase (14) as well as the cholesterylester transfer protein–mediatedtransfer of cholesteryl esters from HDL to LDL (15), which suggeststhat apoA-IV may represent an anti-atherogenic factor. Thisis supported by studies in both humans and mice. Fat-fed micethat overexpress either human (16) or mouse apoA-IV (17) developedsignificantly fewer atherosclerotic lesions in the aorta thancontrol mice. This was even observed when apoA-IV was overexpressedin apoE-deficient mice—that is, in a highly atherogenicbackground (16). In line with these data, we recently demonstratedfor the first time in two independent populations that patientswith angiographically verified coronary artery disease (CAD)have markedly lower apoA-IV concentrations when compared withcontrols (18).
A few studies have investigated apoA-IV in renal patients. Nestelet al. (19) as well as Seishima and Muto (20) described markedlyelevated apoA-IV concentrations in small groups of patientsreceiving hemodialysis and continuous ambulatory peritonealdialysis. This was confirmed by Dieplinger et al. (21), whoobserved significant differences in the plasma distributionof apoA-IV with an accumulation of apoA-IV in HDL when comparedwith controls. They suggested that this altered distributionreflects impaired reversed cholesterol transport in these patients(22). In a large multicenter study that included 534 patientsreceiving hemodialysis and 168 patients receiving continuousambulatory peritoneal dialysis, we observed about twofold elevatedapoA-IV concentrations when compared with controls (23). Assoon as end-stage renal disease was reached, apoA-IV concentrationsdid not differ between the two dialysis treatment modalitiesor between patients with and without diabetes (23).
To our knowledge, however, apoA-IV has not been investigatedin mild and moderate renal failure. It is not known in whichstage of renal impairment apoA-IV starts to increase and whetherit is associated with atherosclerotic complications in thispatient population. Therefore, we investigated a group of 227patients with primary renal disease (24); those with a nephroticsyndrome were excluded. True GFR was determined by using iohexolclearance.
Patients
Patients were recruited during 1997 from eight nephrology departmentsin Germany (Göttingen, Greifswald, Heidelberg, Homburg/Saar,and Munich), Austria (Feldkirch and Innsbruck), and South Tyrol(Bozen), with nearly two-thirds of the patients from two departments(Heidelberg and Innsbruck) (24). We included white patientsaged 19 to 65 yr who had visited the outpatient department atleast once during the preceding year. Exclusion criteria wereserum creatinine >6 mg/dl, diabetes mellitus, malignancy,liver, thyroid or infectious disease at the time of recruitment,nephrotic syndrome (defined as daily proteinuria >3.5 g/1.73m2), organ transplantation, allergy to ionic contrast media,and pregnancy. Three hundred forty patients fulfilled the criteria.Of these, 28 could not be reached, and 85 refused to participatein the study. The remaining 227 patients were included. Theircharacteristics are provided in Table 1. The study was approvedby the institutional ethic committees, and subjects providedwritten informed consent.
Table 1. Characteristics of patients with renal disease and age- and gender-matched controlsa
To avoid interobserver differences, all renal patients wererecruited by one doctor (EK) who visited all the participatingcenters. Patient history, including atherosclerosis events,was recorded by interview and confirmed with patient records.The atherosclerosis events were defined as myocardial infarction,aortocoronary bypass, percutaneous transluminal coronary angioplasty,angiographically verified stenosis of the coronary arteries,stroke, or a symptomatic stenosis of the peripheral arterialvessels (carotis, aortoiliac, or femoral arteries). Each patientunderwent a physical examination. The primary cause of renaldisease was glomerulonephritis in 97 patients (confirmed bybiopsy in 90 patients), polycystic kidney disease in 37 patients,chronic pyelonephritis in 24 patients, other types of renaldisease in 43 patients, and unknown in 26 patients.
Patients were compared with 227 age- and gender-matched whitecontrols of the same ethnic origin without renal impairmentor liver disease who were recruited in 1997 from one of thePROCAM study centers (25).
Laboratory Procedures
Serum and ethylenediaminetetraacetate plasma were taken aftera 12-h overnight fast. After low-speed centrifugation, sampleswere frozen and kept at -80°C before analysis (26). Dependingon the serum creatinine level, two to three blood samples forthe determination of GFR by the iohexol method (27) were obtainedafter infusion of iohexol during the same visit in the outpatientdepartment. We calculated the GFR in 18 patients with mostlyadvanced impairment of renal function by using the formula ofCockcroft and Gault (28). Patients received careful instructionsregarding the collection of 24-h urine samples, which we plannedto use to determine proteinuria.
Measurements of apoA-IV, lipoprotein(a) (Lp(a)), lipids, serumalbumin, GFR, C-reactive protein, and apolipoprotein(a) (apo(a))phenotyping were performed in a central laboratory to avoidinterlaboratory differences in measurements. At this time, thelaboratory staff involved in the study was unaware of the patients’renal function or history; the status of the measured samplesas from patient or control was also unknown to the staff.
Plasma apoA-IV concentrations were determined with an enzyme-linkedimmunosorbent assay that uses affinity-purified rabbit anti-humanapoA-IV polyclonal antiserum as the capture antibody and thesame antibody coupled to horseradish peroxidase as detectionantibody (26,29). Plasma with known content of apoA-IV (standardizedwith purified apoA-IV after phenylalanine quantification byhigh-pressure liquid chromatography) served as calibration standard.Intra-assay and interassay coefficients of variation of thisassay were 4.5 and 6.6%, respectively (26). Samples from thepatients and controls were analyzed as duplicates within oneseries in a blinded fashion and after a similar time of samplestorage at -70°C. Lp(a) quantification and apo(a) phenotypingwere performed as recently described in detail (24). Serum albumin(brom-cresol green method), total and HDL cholesterol, and triglycerideswere measured with kits from Roche (Basel, Switzerland). Measurementswere made on microtiter plates as described previously (26).LDL cholesterol was calculated according to the Friedewald formula.C-reactive protein was measured on a Behring BNA nephelometerwith reagents purchased from Behring Diagnostics (N Latex CRPMono; Behring Diagnostics, Marburg, Germany). The lower detectionlimit of this test was 0.02 mg/dl.
Statistical Analyses
Statistical analyses were performed with SPSS for Windows version10.0 (SPSS, Chicago, IL). Univariate comparisons of continuousvariables between controls and renal patients were performedby unpaired t test or the nonparametric Wilcoxon rank-sum testin case of non-normally distributed variables. Dichotomizedvariables were compared by Pearson’s 2 test. ANOVA wasused to compare continuous variables between controls and renalpatients subgrouped by the three tertiles of GFR. Non-normallydistributed variables were logarithmically transformed beforeinclusion into the analysis.
The Spearman correlation test was used to correlate apoA-IVwith other continuous variables. Adjustment of apoA-IV serumconcentrations for age and proteinuria in patients was performedby linear regression analysis. Multiple regression analysiswas used to investigate the associations of different variableswith apoA-IV serum concentrations. Logistic regression analysiswas performed to identify predictors for previous atheroscleroticevents in patients with renal disease.
Influence of Renal Function on ApoA-IV Concentrations
Renal patients differed from healthy controls by significantlyhigher serum levels of total cholesterol, triglycerides, Lp(a),and apoA-IV and significantly lower concentrations of apoA-Iand apoB, but not by HDL and LDL cholesterol (Table 2). Oneof the most pronounced differences was the 70% higher mean apoA-IVconcentration in patients than in controls (24.6 ± 8.6versus 14.6 ± 4.2 mg/dl, P < 0.001).
Table 2. Serum concentrations of lipids, lipoproteins, and apolipoproteins in controls and patients with renal diseasea
Serum concentrations of apoA-IV had strong and significant inversecorrelations with parameters of renal function so that apoA-IVconcentrations increased with decreasing renal function (serumcreatinine r = 0.73, serum urea r = 0.66, GFR r = -0.62, dailyproteinuria r = 0.37, all P < 0.001) (Figure 1). The correlationswith age (r = 0.20, P < 0.01), total cholesterol (r = 0.13,P < 0.05), apoA-I (r = 0.14, P < 0.05), and Lp(a) (r =0.14, P < 0.05) were much weaker. After adjustment for ageand proteinuria, the correlation of apoA-IV with renal functionbut not correlations with variables of lipoprotein metabolismremained significant (serum creatinine r = 0.56, serum urear = 0.56, GFR r = -0.54, all P < 0.001).
Figure 1. Correlation of apolipoprotein A-IV (apoA-IV) serum concentrations with parameters of renal function (serum creatinine, serum urea, GFR, and daily proteinuria).
We calculated the apoA-IV concentrations in three strata ofrenal function to investigate at which phase of renal impairmentapoA-IV concentrations start to increase (Table 3). We thereforegrouped renal patients according to the tertiles of GFR (i.e.,>90, 45 to 90, and <45 ml/min per 1.73 m2). ApoA-IV concentrationsincreased significantly with decreasing renal function (P <0.001 by ANOVA). ApoA-IV was already increased in the groupof patients with primary renal disease, but GFR values werestill in the normal range (>90 ml/min per 1.73 m2) when comparedwith healthy controls (17.7 ± 6.2 versus 14.6 ±4.2 mg/dl, P < 0.001). These associations remained significantwhen apoA-IV concentrations in patients were adjusted for ageand proteinuria. We also determined whether the primary causeof renal disease influences apoA-IV concentrations. Patientswith polycystic kidney disease showed a trend to slightly higherapoA-IV concentrations when compared with those with glomerulonephritis(25.6 ± 8.8 versus 23.0 ± 8.1 mg/dl, P = 0.11).However, when we adjusted apoA-IV concentrations for differencesin GFR and proteinuria, these two patient groups did no longerdiffer by apoA-IV levels (24.5 ± 6.7 versus 23.5 ±7.1 mg/dl, P = 0.48).
Table 3. Mean ± SD apolipoprotein A-IV (apoA-IV) serum concentrations in controls and patients with renal disease
In a next step, we used multiple regression analysis to assesswhich variables were significantly associated with apoA-IV concentrationsin renal patients. Because GFR, serum creatinine, and serumurea are strongly correlated, we calculated three differentmodels that showed very similar results (the model consideringGFR is presented in Table 4). ApoA-IV showed the strongest associationswith the parameters of renal function (GFR, serum creatinine,or serum urea), which explained approximately 35% of the apoA-IVconcentrations. Further, but much smaller, contributions tothe apoA-IV levels came from proteinuria and apoA-I (Table 4).
Table 4. Association of variables with apoA-IV serum concentrations in patients with mild and moderate renal failurea
ApoA-IV and Atherosclerotic Complications
Finally, we analyzed the association between apoA-IV concentrationsand a history of atherosclerotic complications in renal patients.Twenty-six patients experienced 36 atherosclerotic events, including17 coronary events (mostly myocardial infarctions and aortocoronarybypasses), nine strokes, and 10 events that affected the peripheralarterial system. In univariate analysis, patients with atheroscleroticcomplications showed a trend to lower apoA-IV concentrationswhen compared with the patients without complications (24.9± 8.7 versus 22.3 ± 7.7 mg/dl, P = 0.15). Thisdifference was statistically significant in the stratum withthe worst GFR (31.1 ± 5.8 versus 27.0 ± 7.5 mg/dl,P = 0.04). We also performed a logistic regression analysisfor the entire patient group, including the GFR in the analysis.The most parsimonious model identified three variables associatedwith atherosclerotic complications: age, apoA-IV, and gender(Table 5). Each 1 mg/dl increase of apoA-IV decreased the oddsratio for an atherosclerotic complication by 8% (P = 0.011).The low molecular weight apo(a) phenotype and GFR showed a borderlineassociation with atherosclerotic complications (Table 5). Othervariables (e.g. smoking, hypertension, lipoprotein variables)did not significantly discriminate between affected and unaffectedpatients.
Table 5. Logistic regression analysis investigating the predictive value of apolipoprotein A-IV serum concentrations and other variables for atherosclerotic eventsa
Influence of Renal Function on ApoA-IV Concentrations
The study presented here demonstrates that renal function stronglyeffects apoA-IV serum concentrations. Earlier studies had revealedthat patients with end-stage renal disease have a pronouncedincrease of apoA-IV concentrations (19–21,23). However,it has so far been unknown that even renal disease with GFRvalues in the normal range is accompanied by a significant increasein apoA-IV concentrations. It therefore seems that apoA-IV isan early marker of renal impairment, indicating that its elevationmight be caused by a diminished renal catabolism. This hypothesisis supported by two observations. First, studies in rats showedthat apoA-IV is catabolized by kidney and liver. Histologicanalysis found apoA-IV to be localized within proximal tubularcells (30). Because of its molecular weight of approximately46 kD, apoA-IV can be filtered in the glomeruli at least inits lipoprotein-unbound (free), and hence predominant, form(3,4). An uptake by proximal tubular cells could then be followedby degradation. Whether the catabolic pathway in humans is thesame as in rats remains to be determined, however. Second, becauseapoA-IV is already elevated in the earliest stages of renaldisease when GFR is still normal—or at most, slightlysubnormal—it is likely that the elevation is not simplycaused by an impaired GFR. Disturbance of renal functions notreflected by whole kidney GFR is conceivable. Immunohistochemicalstudies will help clarify this point.
An alternative, but less likely, explanation for the elevatedapoA-IV levels is that apoA-IV is not fully functionally activein renal disease. Uremia could have an influence on, for example,the enzyme-activating and antioxidative properties of apoA-IV.An elevation of apoA-IV protein concentration might be viewedas a compensatory response to functional impairment of apoA-IV.
The influence of renal function on apoA-IV concentrations mightbe the reason why a study by Sun et al. (31) in middle-agedand elderly men and women identified age and diabetes mellitusas major determinants of apoA-IV concentrations. The correlationwith age might mainly be explained by age-dependent changesin renal function. In contrast to the data by Sun et al. (31),we did not observe any significant correlation with age in ourcontrol group recruited from the PROCAM study (r = 0.057, P= 0.39). This can be explained by the fact that we excludedcontrols with renal impairment defined by a serum creatinine>1.5 mg/dl, macroalbuminuria, or both. Similarly, we assumethat the reported elevation of apoA-IV in patients with diabetes(31) is explained by the fact that renal function is impairedin many patients with diabetes mellitus. Diabetes mellitus wasan exclusion criterion in our study. We did also not observeany differences in apoA-IV levels in an earlier study of dialysispatients when 189 patients with diabetes mellitus were comparedwith 513 patients without diabetes (23). Other studies in patientswith diabetes mellitus, however, reported an elevation of apoA-IVbut failed to assess renal function (32,33). This clearly indicatesthe need for thorough controlling of apoA-IV concentrationsfor renal function in case control studies. If renal functionis not considered, the interpretation of results can be misleadingwhen differences in renal function exist between cases and controls.
ApoA-IV and Atherosclerotic Complications
We recently reported for the first time significantly lowerapoA-IV levels in 114 white men with angiographically definedCAD compared with 114 age-adjusted male controls (10.2 ±3.8 mg/dl versus 15.1 ± 4.0 mg/dl, P < 0.001). Thisinverse relationship between apoA-IV levels and the presenceof CAD was confirmed in an independent sample of 68 Asian Indianmen with angiographically documented CAD and 68 age-matchedcontrols. In line with this finding, we observed lower apoA-IVconcentrations in renal patients who had already experiencedan atherosclerotic event when compared with those without anevent. In the logistic regression analysis, apoA-IV emergedas a significant and independent predictor for the presenceof atherosclerotic events (Table 5). The cross-sectional studydesign, however, may underestimate the association of atherosclerosisrisk with low apoA-IV levels because only survivors of eventscould be studied. Of course, larger and prospective investigationswill be necessary to definitively prove this association andto obtain data investigating a possible causality. Nevertheless,there is strong mechanistic a priori evidence that makes thisassociation highly likely: cell culture studies showed the involvementof apoA-IV in several steps of the reverse cholesterol transport(4,9–14) and document its antioxidative properties (34);overexpression of human and mouse apoA-IV in mice inhibitedthe development of atherosclerosis (16) and reduced oxidationparameters in vivo (17,35); and finally, first results demonstratedlower apoA-IV concentrations in men with angiographically provenCAD (18).
The results of this and another study (18) are in contrast tothe results of an investigation in patients with non–insulin-dependentdiabetes mellitus that described significantly higher apoA-IVconcentrations in patients with macrovascular complicationscompared with those without macrovascular complications (33).As previously discussed (18), the explanation for this discrepancymight be the increased prevalence of microalbuminuria and theconcomitant renal impairment in patients with diabetes withmacrovascular complications. The authors excluded patients withrenal failure, but they did not provide detailed informationabout the exclusion criteria. However, approximately 40% ofthe patients had microalbuminuria (33), pointing at least toa renal involvement expected to significantly affect apoA-IVconcentrations. We clearly showed in this study that even renaldisease with GFR values in the normal or subnormal range isaccompanied by a significant increase in apoA-IV concentrations.Because patients with diabetes with macrovascular complicationsare more likely to have renal involvement than patients withdiabetes without vascular disease, high levels of apoA-IV inpatients with diabetes with macrovascular complications maysimply reflect their impaired renal function.
Paradox of High ApoA-IV Concentrations in Uremia, a State of High Cardiovascular Risk
One might ask why patients with renal disease have such an excessiverisk for atherosclerotic complications (36) when they have suchhigh apoA-IV concentrations. If apoA-IV has indeed antiatherogenicproperties, these patients should be more protected than nonrenalpatients. This argument is intriguing from a univariate pointof view. We should keep in mind, however, that these patientshave numerous other atherosclerosis risk factors yielding anunfavorable overall profile (36). Besides the changes in traditionalatherosclerosis risk factors, we and others demonstrated markedchanges for Lp(a) and homocysteine (for reviews, see [37,38]),even at very early stages of renal disease when GFR is normalor minimally reduced at best (24,39,40).
Several studies demonstrated that homocysteine as well as Lp(a)and especially Lp(a) of low molecular weight apo(a) phenotypesare important risk factors for atherosclerosis in these patients(41–49). Whether apoA-IV counteracts this burden is notyet determined, but it would be in line with our observationof lower apoA-IV levels in renal patients with a history ofatherosclerotic events. A recent discussion focused on the issuewhether renal insufficiency per se is a marker for already establishedgeneralized atherosclerosis or whether it is a proatherogenicstate (50). This discussion was mainly based on the prospectiveresults from the Framingham Study in subjects with little comorbiditythat failed to identify renal insufficiency as an independentrisk factor for subsequent cardiovascular disease when the datawere adjusted for traditional cardiovascular risk factors andpresence of cardiovascular disease (51). One may speculate thatin renal insufficiency, apoA-IV and possibly other protectingfactors offset potentially atherogenic circulating mediatorsassociated with renal insufficiency, so that the proatherogeniccharacter of renal failure is obscured.
ApoA-IV: A Surrogate for ApoA-I?
It is an interesting observation that patients with renal diseasein our study had normal HDL cholesterol values but markedlydecreased apoA-I levels. Past studies that investigated patientswith more advanced renal failure described decreased HDL cholesterolconcentrations (23,52–54). In contrast, the patients westudied had a mean GFR of approximately 70 ml/min per 1.73 m2.We propose that the decrease in HDL cholesterol is precededby an apoA-I depletion or a lipid particle accumulation of HDLcholesterol consistent with an impaired reverse cholesteroltransport pathway. Because apoA-I and apoA-IV show substantialfunctional overlap (e.g., lecithin:cholesterol acyltransferaseactivation), it remains to be determined whether an increaseof apoA-IV is a homeostatic attempt to compensate the decreaseof the apoA-I. In-depth studies of reverse cholesterol transportin the early stages of renal disease are obviously indicated.
In summary, our data clearly show that apoA-IV starts to increaseduring the earliest phases of renal insufficiency, which makesapoA-IV an early marker of renal impairment. On the other hand,low apoA-IV concentrations seem to be associated with atheroscleroticcomplications in patients with mild to moderate renal failure.
Acknowledgments
FK is supported by the Austrian Program for Advanced Researchand Technology (APART) of the Austrian Academy of Science andby the Knoll William Harvey Prize. This study was supportedby grants from the Austrian Science Fund (P14717-GEN), the ÖsterreichischerHerzfonds, the Dr. Legerlotz Stiftung, and the D. Swarovski/Raiffeisenfoundation (FK). The support of Else Kröner-Fresenius Stiftungand of a grant from the Forschungskommission Medizinische FakultätRuperto-Carola-Universität Heidelberg are gratefully acknowledged.
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Received for publication June 19, 2001.
Accepted for publication September 21, 2001.
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Top
Abstract
Introduction
2 test. ANOVA was used to compare continuous variables between controls and renal patients subgrouped by the three tertiles of GFR. Non-normally distributed variables were logarithmically transformed before inclusion into the analysis. 
