 |
||||
| 2007 JASN IMPACT FACTOR 7.111 | HOME AUTHOR INFO EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP | |||
| CURRENT ISSUE | ARCHIVES | JASN Express | ONLINE SUBMISSION | |
|
||||
| 2007 JASN IMPACT FACTOR 7.111 | HOME AUTHOR INFO EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP | |||
| CURRENT ISSUE | ARCHIVES | JASN Express | ONLINE SUBMISSION | |
*
Institute of Medical Biology and Human Genetics, University of Innsbruck,
Austria
Department of Internal Medicine, Division of Nephrology,
Ruperto-Carola-University, Heidelberg, Germany
Institute of Clinical Chemistry and Laboratory Medicine and Institute of
Arteriosclerosis Research, University of
Münster, Germany
§
Innsbruck University Hospital, Department of Clinical Nephrology,
Innsbruck, 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, Feldkirch,
Austria
Medizinische Universitätskliniken des
Saarlandes, Innere Medizin IV, Homburg/Saar, Germany
Bozen Hospital, Division of Nephrology and Hemodialysis, Bozen,
Italy.
Correspondence to Dr. Florian Kronenberg, Institute of Medical Biology and Human Genetics, University of Innsbruck, Schöpfstrasse 41, A-6020 Innsbruck, Austria. Phone: +43 512 507 3474; Fax: +43 512 507 2861; E-mail: Florian.Kronenberg{at}uibk.ac.at
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Two prospective studies in hemodialysis patients identified Lp(a) concentrations and/or the apo(a) phenotype as one of the most important risk factors for cardiovascular disease in this high-risk group for atherosclerosis (14,15). Since cardiovascular disease is by far the most frequent cause of death in these patients (16), this lipoprotein is a valuable diagnostic risk marker (17).
Genetic determination of Lp(a) concentrations was estimated to range from 70% to more than 90% (4,5,6,18). High genetic determination combined with the wide range of Lp(a) concentrations makes it difficult to assess the impact of nongenetic factors on Lp(a) levels. Recently, we provided mathematical proof that a substantial number of subjects are necessary to quantitatively assess nongenetic determinants of Lp(a) levels with reliability. This is especially the case when a study is not controlled for apo(a) isoforms (19,20). Two of the most important nongenetic factors influencing Lp(a) concentrations are nephrotic-range proteinuria and end-stage renal disease (19). Patients with nephrotic syndrome show the highest elevations of Lp(a) among all known pathologic conditions (21,22). Dialysis patients treated with continuous ambulatory peritoneal dialysis (CAPD) show significantly higher levels than those treated with hemodialysis (19,20). Large studies in hemodialysis patients found that only patients with HMW apo(a) phenotypes experience a relative increase of Lp(a) when compared to apo(a) phenotype-matched control subjects, but not those with LMW apo(a) phenotypes (20,23,24,25). Besides an increase of Lp(a) in CAPD patients with HMW apo(a) phenotypes, those with LMW types showed increased (24), or at least a tendency (20) to increased, levels when compared to phenotype-matched control subjects.
Studies in patients with advanced or predialytic stages of renal disease clearly described elevated Lp(a) concentrations (24,26,27,28,29,30,31,32,33). Investigations that included patients with early stages of renal disease were contrasting and described unchanged (30) or elevated Lp(a) levels (27). Some of these reports found a correlation between Lp(a) levels and serum creatinine concentrations or GFR (27,29), but these findings were not confirmed by others (26,30,31). Most studies were small, sometimes comprising no more than 10 to 20 patients in each subgroup, and only two consider the apo(a) size polymorphism as a confounding factor (24,34). One study investigated patients recruited for essential hypertension and described higher Lp(a) levels in hypertensive patients with renal impairment but the patients did not have primary renal disease (35). In a subgroup of these patients, a strong genetic association between LMW apo(a) phenotypes and the prevalence of end-organ damage was noted (34). Milionis et al. included patients with more advanced renal failure (creatinine clearance, 10 to 60 ml/min) and calculated creatinine clearance instead of measuring true GFR (24).
We investigated a group of 227 patients with primary renal disease excluding those with nephrotic syndrome. GFR was determined by iohexol clearance. We addressed the following questions: (1) Do Lp(a) concentrations change when GFR is reduced? (2) Does the type of primary renal disease influence Lp(a) levels? (3) Is Lp(a) elevated in all apo(a) phenotype groups? (4) Is an acute phase reaction necessary to observe elevated levels of Lp(a) in these patients?
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
To avoid interobserver differences, all renal patients were recruited by one physician (E.K.) who visited the participating centers. Each patient's history was recorded during an interview and compared with his or her records. All patients underwent a physical examination. The primary cause of renal disease was glomerulonephritis in 97 patients (biopsy confirmed in 90 cases), polycystic kidney disease in 37, chronic "pyelonephritis" in 24, other types of renal disease in 43, and unknown in 26.
Patients were compared with 227 age- and gender-matched Caucasian control subjects of the same ethnic origin without renal impairment or liver disease who were recruited in 1997 from one of the PROCAM study centers (36).
Laboratory Procedures
Serum and ethylenediaminetetra-acetic acid plasma were taken after a 12-h
overnight fast. After low-speed centrifugation, samples were frozen and kept
at -80°C before analysis
(37). Depending on the serum
creatinine level, two to three blood samples for the determination of GFR by
the iohexol method (38) were
obtained after infusion of iohexol during the same visit in the outpatient
department. We calculated in 18 patients with mostly advanced impairment of
renal function the GFR using the formula of Cockroft and Gault
(39). Patients were carefully
instructed about the collection of a 24-h urine sample for the determination
of proteinuria.
Measurement of Lp(a), serum albumin, GFR, C-reactive protein (CRP), and apo(a) phenotyping were performed each centrally in a single laboratory, respectively, to avoid interlaboratory differences in measurements. At this time, the laboratory staff involved in the study was unaware of the patient's renal function and the patient/control status of the measured samples.
Lp(a) quantification was performed as described in detail (37) with a double-antibody enzyme-linked immunosorbent assay (ELISA), using an affinity-purified polyclonal apo(a) antibody for coating and the horseradish peroxidase-conjugated monoclonal 1A2 for detection. An Lp(a)-positive serum from Immuno (Vienna, Austria) with the same apo(a) isoforms served as standard throughout the study. Each sample was analyzed in duplicate, and intra- and interassay coefficients of variation were 2.7 and 6%, respectively. Serum albumin (bromcresol green method) was measured using a kit from Boehringer Mannheim (Mannheim, Germany). Measurements were made on microtiter plates as described previously (37). Adjustment of Lp(a) concentrations for hematocrit had no major impact on our findings (40). CRP was measured on a Behring BNA nephelometer, using reagents from Behring Diagnostics (N Latex CRP mono; Behring Diagnostics, Marburg, Germany). The lower detection limit of this test was 0.02 mg/dl.
Apo(a) phenotyping was performed by sodium dodecyl sulfate-agarose gel electrophoresis (SDS-agarose) under reducing conditions as outlined (41) with slight modifications. Fifty nanograms of Lp(a) was applied to the gel when serum Lp(a) concentrations were above 4 mg/dl. With lower concentrations, a fixed volume of 1.5 µ1 of serum was applied to the gel. Electrophoresis was followed by immunoblotting (2), using the monoclonal antibody 1A2 for detection of apo(a) isoforms.
Calculation of the Lp(a) Concentration Derived from each Apo(a)
Isoform
In subjects expressing two apo(a) isoforms, a single investigator (F.K.)
estimated the percent relation of the two isoforms by densitometric scanning
of the apo(a) bands of the immunoblots from SDS-agarose gel electrophoresis.
We used the Lp(a) concentrations measured by ELISA to calculate the
isoform-specific amount of Lp(a) derived from each isoform by using these
densitometric relative estimates. Figure
1 represents an example of this procedure. When an individual with
21 and 33 K-IV repeats had an Lp(a) serum concentration of 40 mg/dl measured
by ELISA, and the 21 K-IV isoform accounted for 85% of the staining in the
SDS-agarose gel electrophoresis, we calculated the Lp(a) concentration
originating from this isoform to be 34 mg/dl (40 x 0.85). The isoform
with 33 K-IV repeats accounted for the remaining 6 mg/dl. The whole Lp(a)
concentration counted for the expressed isoform in case a subject showed only
one apo(a) band.
|
Statistical Analyses
Statistical analyses were performed with Statistical Package for the Social
Sciences (SPSS) for Windows version 7.5.2. Univariate comparisons of
continuous variables between control subjects and renal patients were done by
unpaired t test or the nonparametric Wilcoxon rank sum test in the
case of nonnormally distributed variables. Dichotomized variables were
compared using Pearson's 
2 test or the likelihood ratio
2 test. ANOVA was used to compare continuous variables between
control subjects and renal patients subgrouped by the three tertiles of GFR.
Non-normally distributed variables were logarithmically transformed before
including them in the analysis. The Spearman correlation test was used to
correlate proteinuria and GFR with concentrations of lipids, lipoproteins, and
apolipoproteins, as well as CRP with Lp(a). Adjustment of Lp(a) serum
concentrations for proteinuria and/or GFR in patients was done using linear
regression analysis. Multiple regression analysis was used to investigate the
association of different variables with Lp(a) serum concentrations.
Because of the high number of detectable apo(a) isoforms (>30), many phenotypes were represented only in low numbers. To account for this problem, we decided a priori to combine apo(a) isoforms in steps of three K-IV repeats according to the molecular weight of the smaller apo(a) isoforms to have sufficient sample sizes in each category (42). Because subjects with 11 to 16 or >34 K-IV repeats were represented relatively rarely, we built one group by combining 11 to 19 and another by combining >31 K-IV repeats. Furthermore, we divided apo(a) phenotypes into two subgroups according to the molecular weight of the smaller apo(a) isoforms, as done in previous works (7,9,13,20,23,25,34,43,44,45,46,47). The LMW group included all subjects with at least one apo(a) isoform with 11 to 22 K-IV repeats (48); the HMW group comprised all subjects having only isoforms with more than 22 K-IV repeats. If two apo(a) isoforms were detectable, we used only the smaller apo(a) isoform for categorization, which we discussed recently in detail (47). In a subanalysis, however, we considered the effect of the second apo(a) isoform, if expressed, as described above.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Renal patients had significantly higher Lp(a) serum concentrations when compared to control subjects (mean ± SD; median: 29.5 ± 32.0; 17.9 versus 20.7 ± 32.8; 6.9, P < 0.001) (Table 2). Apo(a) phenotyping was performed to investigate whether the elevation of Lp(a) in renal patients is determined primarily by the apo(a) gene or renal disease. In case of the former, we expected an association of LMW apo(a) isoforms with renal disease. Because we observed in renal patients a similar frequency distribution of apo(a) alleles either in terms of apo(a) K-IV repeats or in terms of LMW and HMW apo(a) phenotypes as in control subjects (Table 2), we concluded that the elevation of Lp(a) is caused by glomerulotubular dysfunction.
|
Influence of Primary Renal Disease
Lp(a) serum levels were compared between patients with glomerulonephritis
and patients with polycystic kidney disease as prototypes of inflammatory and
noninflammatory renal disease, respectively. Crude and Lp(a) serum
concentrations adjusted for proteinuria and GFR as well as the frequency of
LMW apo(a) phenotypes were similar in both groups
(Table 3). Therefore, no
influence of the etiology of renal disease on the Lp(a) levels was
observed.
|
Influence of GFR
The correlation of Lp(a) with GFR (r = -0.18, P <
0.001) was more pronounced than that of Lp(a) with non-nephroticrange
proteinuria (r = 0.14, P < 0.05). We therefore grouped
renal patients according to the tertiles of GFR, i.e., >90 ml/min
per 1.73 m2, 45 to 90 ml/min per 1.73 m2, and <45
ml/min per 1.73 m2. ANOVA showed linearly increasing levels of
Lp(a) with decreasing renal function (first rows of
Table 4). Lp(a) concentrations
tended to be elevated even in the group with GFR >90 ml/min per 1.73
m2 when compared with control subjects; Lp(a) concentrations were
increased significantly in the other two groups with more markedly reduced
renal function. The increase of Lp(a) with decreasing renal function remained
similar when Lp(a) levels were adjusted for proteinuria.
Figure 2 shows the frequency
distribution of Lp(a) concentrations in control subjects and in the three
groups of patients according to the GFR. Approximately 60% of random control
subjects had Lp(a) concentrations <10 mg/dl. This frequency was lower by
half in renal patients with a GFR 
90 ml/min per 1.73 m2.
|
|
Changes of Lp(a) Serum Concentrations in Relation to the Apo(a) Size
Polymorphism
We analyzed whether the relative increase of Lp(a) with decreasing renal
function was related to the apo(a) size polymorphism. To avoid extensive
subgrouping resulting in small group sizes and to render the results
comparable with previous findings, we grouped apo(a) phenotypes into LMW and
HMW apo(a) phenotypes. ANOVA showed no significant differences in the Lp(a)
concentrations in control subjects and renal patients with LMW apo(a)
phenotypes independently of the degree of renal impairment
(Table 4). In striking
contrast, Lp(a) concentrations were markedly increased with decreasing renal
function in patients with HMW apo(a) phenotypes: Compared to control subjects,
mean and median levels were even higher by 70 and 40%, respectively, in renal
patients who still had a GFR >90 ml/min per 1.73 m2
(Table 4). To investigate
whether this increase in Lp(a) was associated with proteinuria rather than
with GFR, we excluded in a subanalysis 11 of the 55 patients with HMW apo(a)
phenotypes who had a daily proteinuria >1 g/1.73 m2. This still
resulted in significantly higher Lp(a) levels in the patient group with GFR
>90 ml/min per 1.73 m2 when compared with control subjects (11.8
± 13.8 mg/dl [median 5.0] versus 8.1 ± 11.8 mg/dl
[median 4.4], P < 0.05). With further impairment of renal
function, Lp(a) increased by three- to fourfold in renal patients with HMW
apo(a) phenotypes and a GFR <45 ml/min per 1.73 m2 when compared
with phenotype-matched control subjects
(Table 4).
The above subgrouping into LMW and HMW apo(a) phenotypes in a given
individual is based on the apo(a) isoform with the lowest molecular weight. It
does not consider that many subjects with an LMW apo(a) phenotype have not
only one LMW, but also one HMW apo(a) isoform. To control for the influence of
the second apo(a) isoform, we calculated based on the measured Lp(a)
concentrations in each subject separately the Lp(a) concentrations arising
from the first and the second apo(a) isoforms by estimating the relative
proportion of the two isoforms in the SDS-agarose gel electrophoresis. The
term "first" simply refers to the isoform with the smaller number
of K-IV repeats in case of two expressed isoforms or the expressed isoform in
subjects who show only one isoform. The "second" isoform means the
isoform with the higher number of K-IV repeats in case of two expressed
isoforms. (For details about the calculation of isoform-specific Lp(a)
concentrations, see Materials and Methods). When the first apo(a) isoform was
of low molecular weight (22 K-IV repeats), we observed that the Lp(a)
concentrations arising from these LMW apo(a) isoforms were similar in control
subjects and all three groups of patients
(Table 5). We found highly
significant increasing Lp(a) concentrations with decreasing renal function in
case the first isoform was already of high molecular weight (>22 K-IV
repeats). A similar but less pronounced increase was observed for the second
apo(a) isoform in renal patients who expressed both isoforms of high molecular
weight. We did not calculate the apo(a) isoform-specific concentrations of
Lp(a) for the second isoform in case it was of low molecular weight, since
this constellation was only met by one or two patients in each subgroup of
renal function.
|
Lp(a) Serum Concentrations in Relation to Acute Phase Reactant
CRP
We investigated whether the apo(a) phenotype-specific elevation of Lp(a) is
related to an acute phase reaction (diagnosed by elevated CRP levels), as
recently suggested for patients with advanced impairment of renal function
(33) or hemodialysis patients
(25). None of our patients was
investigated during obvious acute infection or illness. Only 41 of the renal
patients (18%) had CRP concentrations 
0.5 mg/dl. We found no evidence that
the elevation of Lp(a) was associated with elevated CRP concentrations. No
correlation was observed between the concentration of CRP and Lp(a)
(r = 0.05, P = 0.47).
Figure 3 shows that the
elevation of Lp(a) levels was specific for HMW apo(a) phenotypes regardless of
whether we analyzed the whole patient group or whether we excluded those
patients with elevated CRP serum concentrations. This analysis revealed
similar results when either crude Lp(a) concentrations or Lp(a) levels
adjusted for proteinuria and GFR were considered in the calculations.
|
Correlation of Variables with Lp(a) Serum Concentrations by Multiple
Regression Analysis
We finally investigated in a multiple regression analysis which variables
were associated with Lp(a) serum concentrations in renal patients
(Table 6). The apo(a) phenotype
classification in LMW and HMW apo(a) phenotypes and GFR were significantly
associated with Lp(a) serum concentrations. Proteinuria was not independently
associated with Lp(a) but modified the association between GFR and Lp(a) with
borderline statistical significance, as shown by an interaction term of
proteinuria and GFR. When the analysis was repeated including only patients
with HMW apo(a) phenotypes, we found that GFR was significantly associated
with Lp(a) levels and that the interaction term of proteinuria and GFR showed
again a marginally significant association. Both GFR and the interaction term
of proteinuria and GFR did not contribute to the model in patients with LMW
apo(a) phenotypes.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
In a first step, we excluded that the higher levels of Lp(a) in renal patients were caused by a higher frequency of LMW apo(a) phenotypes in renal patients when compared with control subjects. This would have indicated that the LMW apo(a) phenotype predisposes to specific renal diseases, as noted for example for coronary artery disease (7,8,9,10,11,12,13) or end-organ damage in patients with essential hypertension (34). Dialysis patients with LMW apo(a) phenotypes have a two- to threefold higher prevalence (47,49) as well as incidence (15) of major cardiovascular events than those with HMW apo(a) types. Although we demonstrated already in previous studies (20,23) that dialysis patients have a similar apo(a) phenotype distribution than control subjects, we considered that we could not completely exclude a potential confounding survivor effect in dialysis patients in view of the enormous risk of atherosclerosis in those patients with LMW apo(a) phenotype (15,45,47). We can now exclude a primary genetic cause for the elevated Lp(a) levels with very high probability because patients and matched control subjects had a similar apo(a) phenotype distribution and because the markedly shorter disease duration should have minimized a confounding survivor effect. Furthermore, a primary reason for an elevation of Lp(a) in these patients seems to be less likely due to heterogeneity of renal disease. Indeed, we did not see major differences in the apo(a) phenotype distribution between patients who suffered from glomerulonephritis and polycystic kidney disease.
One of the most interesting findings in this study population is the apo(a) phenotype-specific elevation of Lp(a), which we and others also found in hemodialysis patients (20,23,24,25). This means that Lp(a) in hemodialysis patients is only elevated in patients with HMW apo(a) phenotypes when compared to control subjects with the same apo(a) phenotypes. Patients with LMW apo(a) phenotypes have nearly identical Lp(a) levels as apo(a) phenotype-matched control subjects. The observation in hemodialysis patients is based on the investigation of more than 1000 patients and about 650 control subjects in four studies (20,23,24,25), but was not confirmed by three smaller studies in different populations using different phenotyping methods, Lp(a) assays, and cut-points for categorization of LMW and HMW apo(a) phenotypes (50,51,52). Recently, Milionis et al. studied a group of 68 patients with more advanced renal failure (creatinine clearance 10 to 60 ml/min) and also observed an apo(a) phenotype-specific elevation of Lp(a) (24). Patients and control subjects, however, had an unusually high frequency of LMW apo(a) phenotypes (45.2 and 52.9%, respectively) that was never observed in any other Caucasian population studied thus far (6). In the present study, we observed such phenotype-specific elevation of Lp(a) in renal patients with non-nephrotic proteinuria at all levels of GFR even in the earliest stage of disease when GFR is still normal (>90 ml/min per 1.73 m2). We therefore conclude that this phenomenon is not restricted to hemodialysis patients. One investigation studying 168 CAPD patients showed a trend toward elevated Lp(a) levels in LMW apo(a) phenotypes besides the markedly elevated levels in HMW apo(a) phenotypes (20). A smaller study including only 47 CAPD patients reported elevated levels in both phenotype groups (24). Patients with nephrotic syndrome have a clear elevation of Lp(a) in all apo(a) phenotype classes (21). It therefore seems that a high degree of proteinuria or of protein loss through the peritoneal membrane is related to an increased hepatic synthesis of Lp(a) of all apo(a) isoform classes. We therefore excluded in our analysis all patients with nephrotic-range proteinuria to minimize the risk of confounding the results by heterogeneity of the causes of Lp(a) elevation. We furthermore analyzed the data with and without adjustment of Lp(a) levels for the magnitude of proteinuria. Adjustment did not significantly change the findings. Even exclusion of the patients with a daily proteinuria >1 g/1.73 m2 in the group of patients with HMW apo(a) phenotypes and a GFR >90 ml/min per 1.73 m2 resulted in higher Lp(a) levels in patients when compared to apo(a) phenotype-matched control subjects. We cannot determine with certainty whether this small amount of the remaining proteinuria or the renal disease itself is responsible for the elevation of Lp(a) in this earliest stages of renal disease. Multiple regression analysis in the entire patient group, however, revealed that besides the apo(a) size polymorphism, GFR was significantly associated with Lp(a) serum concentrations. This association between GFR and Lp(a) was marginally modified by non-nephrotic-range proteinuria, but proteinuria itself did not significantly contribute to the model. This is in contrast to nephrotic syndrome, which has a tremendous influence on Lp(a) levels (21,22). A certain amount of proteinuria therefore might be necessary to show an independent association with Lp(a) levels. In the case of non-nephrotic proteinuria, proteinuria at the very most modifies the association between GFR and Lp(a) levels.
Because most subjects express two apo(a) isoforms and because HMW apo(a) isoforms are more common than LMW ones, LMW apo(a) phenotypes express according to our definition (see Materials and Methods) a second, mostly less intensive HMW apo(a) isoform in about 60% of the cases. To exclude that this second isoform could have influenced our findings in patients with LMW apo(a) phenotypes, we calculated the amount of Lp(a) originating from each isoform based on the percent distribution of the two isoforms on SDS-agarose gel electrophoresis. This more sophisticated analysis demonstrated that Lp(a) concentrations derived from the LMW apo(a) isoform are not influenced by renal disease. However, there are two possible pitfalls. First, chemiluminescence analysis for visualizing apo(a) bands might not be linear over a wide range. This could indeed be a problem if we would apply from each person the same amount of serum to the gel as done in many phenotyping methods. In contrast, we first measure Lp(a) and apply for each person the individual amount of serum resulting in the same amount of Lp(a) on the gel. This amount was determined to be markedly below the maximum intensity of the signal. By always applying the same amount of Lp(a), we avoid reaching the maximum signal and narrow the range in the signal and therefore the problem of linearity. The second pitfall involves the immunoreactivity of apo(a) antibodies directed against repetitive epitopes of apo(a). When an antibody such as our 1A2 is directed against the repetitive K-IV, it does not necessarily mean that the antibody recognizes one molecule of apo(a) several times. This cannot be expected due to steric hindrance, and this was also not observed in a recent publication (53). It is even conceivable that an antibody, although directed against a repetitive antibody, detects Lp(a) isoform-independent when the steric configuration allows only the binding of one antibody to one molecule of Lp(a). We do not have evidence that our antibody recognizes one molecule of apo(a) several times. It must be further pointed out that we did not use the densitometric scanning of apo(a) bands to measure Lp(a) concentrations of each isoform. We used this method simply to determine the relative proportion of the isoforms in heterozygote subjects. This proportion was then used to calculate the Lp(a) serum concentration for each apo(a) isoform based on the exact Lp(a) concentrations measured by ELISA. This approach, reported here for the first time, was an attempt to minimize the confounding of results by the second apo(a) isoform. In case the above discussed pitfalls still played a role, serum samples of both patients and control subjects were exposed to them in the same way, which makes this attempt nevertheless reliable.
Recently, Stenvinkel and colleagues investigated a group of patients immediately before the start of renal replacement therapy with a creatinine clearance of 9 ± 1 ml/min. They found elevated levels of Lp(a) and suggested that uremia causes an increase of Lp(a) by an unknown mechanism (33). We conclude from our data that a uremic status is not mandatory for elevated Lp(a) levels in patients with renal disease. We even observed an elevation of Lp(a) in patients with HMW apo(a) phenotypes who suffered from a primary renal disease but still had a normal GFR (>90 ml/min per 1.73 m2). The GFR in these very early stages of renal disease, however, may mask nephron loss because of a compensatory increase of single-nephron GFR (54). This would be compatible with the notion that the increase of Lp(a) in these patients does not result from diminished filtration per se, but from diminished parenchymal and metabolic function (e.g., related to Lp(a) degradation). Degradation of Lp(a) in the kidney is suggested by large concentration differences of Lp(a) between the aorta and the renal vein (55) and the finding of apo(a) fragments in urine (56,57). Because these fragments have a molecular weight of up to more than 200 kD (56,57), at least the larger apo(a) fragments must have entered the postglomerular space via tubular mechanisms, mostly via active transport. With further progression of renal disease and the accompanying decrease of GFR, Lp(a) increases further. We propose that impaired catabolism of Lp(a) is the cause of increased Lp(a) concentrations in non-nephrotic renal patients. Turnover studies with stable isotope technique are necessary to confirm this hypothesis and exclude increased hepatic synthesis as an alternative possibility. Using this technique, increased hepatic synthesis of Lp(a) independent of the apo(a) isoform size has been demonstrated in patients with nephrotic syndrome (58).
Kario et al. reported in a small group of hemodialysis patients
that high levels of CRP, sialic acid, and interleukin-6 are closely related to
the elevated Lp(a) levels, however, apo(a) size polymorphism was not taken
into consideration (59).
Nevertheless, such a relation would be intriguing and mechanistically
plausible since several interleukin-6-responsive elements were described in
the 5' flanking regulatory region of the apo(a) gene
(60). Some studies described
that Lp(a) concentrations behave as an acute phase reactant
(61,62).
Zimmermann and colleagues recently suggested that the apo(a)
phenotype-specific elevation of Lp(a) in hemodialysis patients is explained by
a state of microinflammation, also reflected by elevated CRP and serum amyloid
A levels (25). This cannot be
the entire explanation, however, because an elevation of Lp(a) was also seen
in hemodialysis patients with HMW apo(a) phenotypes and normal CRP and normal
serum amyloid A levels. Their Lp(a) concentration was still significantly
higher than in control subjects, but lower than in hemodialysis patients with
elevated CRP and serum amyloid A levels
(25). When we analyzed our
data in relation to CRP levels measured with a highly sensitive assay, we
observed that only 18% of the renal patients had CRP levels in the pathologic
range (0.5 mg/dl). An apo(a) phenotype-specific elevation of Lp(a) was
noted even when we excluded these patients. We therefore conclude that an
acute phase reaction measured by elevated CRP levels at the very most modifies
Lp(a) concentrations, but fails to explain the apo(a) phenotype-specific
elevation of Lp(a) at least in patients with mild and moderate impairment of
renal function.
In summary, our data show that apo(a) phenotype-specific elevation of Lp(a) occurs in patients with renal disease and non-nephrotic proteinuria even when GFR is still normal. How such moderate damage to the kidney impairs Lp(a) metabolism requires additional studies.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  E. Ritz and C. Wanner Lipid Abnormalities and Cardiovascular Risk in Renal Disease J. Am. Soc. Nephrol., June 1, 2008; 19(6): 1065 - 1070. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Romayne Kurukulasuriya, G. Athappan, G. Saab, A. Whaley Connell, and J. R. Sowers Review: HMG CoA reductase inhibitors and renoprotection: the weight of the evidence Therapeutic Advances in Cardiovascular Disease, October 1, 2007; 1(1): 49 - 59. [Abstract] [PDF]
|
|
|
|
 |
|
 B. Dieplinger, A. Lingenhel, N. Baumgartner, W. Poelz, H. Dieplinger, M. Haltmayer, F. Kronenberg, and T. Mueller Increased Serum Lipoprotein(a) Concentrations and Low Molecular Weight Phenotypes of Apolipoprotein(a) Are Associated with Symptomatic Peripheral Arterial Disease Clin. Chem., July 1, 2007; 53(7): 1298 - 1305. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. C.H. Kwan, F. Kronenberg, S. Beddhu, and A. K. Cheung Lipoprotein Metabolism and Lipid Management in Chronic Kidney Disease J. Am. Soc. Nephrol., April 1, 2007; 18(4): 1246 - 1261. [Full Text] [PDF]
|
|
|
|
|
|
E. Ritz and C. Wanner Lipid Changes and Statins in Chronic Renal Insufficiency J. Am. Soc. Nephrol., December 1, 2006; 17(12_suppl_3): S226 - S230. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Amann, C. Wanner, and E. Ritz Cross-Talk between the Kidney and the Cardiovascular System J. Am. Soc. Nephrol., August 1, 2006; 17(8): 2112 - 2119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Boes, D. Fliser, E. Ritz, P. Konig, K. Lhotta, J. F.E. Mann, G. A. Muller, U. Neyer, W. Riegel, P. Riegler, et al. Apolipoprotein A-IV Predicts Progression of Chronic Kidney Disease: The Mild to Moderate Kidney Disease Study J. Am. Soc. Nephrol., February 1, 2006; 17(2): 528 - 536. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Fliser, F. Kronenberg, J. T. Kielstein, C. Morath, S. M. Bode-Boger, H. Haller, and E. Ritz Asymmetric Dimethylarginine and Progression of Chronic Kidney Disease: The Mild to Moderate Kidney Disease Study J. Am. Soc. Nephrol., August 1, 2005; 16(8): 2456 - 2461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Knight, E. B. Rimm, J. K. Pai, K. M. Rexrode, C. C. Cannuscio, J. E. Manson, M. J. Stampfer, and G. C. Curhan Kidney Dysfunction, Inflammation, and Coronary Events: A Prospective Study J. Am. Soc. Nephrol., July 1, 2004; 15(7): 1897 - 1903. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Ritz and W. M. McClellan Overview: Increased Cardiovascular Risk in Patients with Minor Renal Dysfunction: An Emerging Issue with Far-Reaching Consequences J. Am. Soc. Nephrol., March 1, 2004; 15(3): 513 - 516. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. A. Kaysen and J. P. Eiserich The Role of Oxidative Stress-Altered Lipoprotein Structure and Function and Microinflammation on Cardiovascular Risk in Patients with Minor Renal Dysfunction J. Am. Soc. Nephrol., March 1, 2004; 15(3): 538 - 548. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 |
