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J Am Soc Nephrol 12:1052-1058, 2001
© 2001 American Society of Nephrology

Impact of Apolipoprotein(a) Phenotypes on Long-Term Renal Transplant Survival

FRIEDERIKE WAHN*, VOLKER DANIEL{dagger}, FLORIAN KRONENBERG{ddagger}, GERHARD OPELZ{dagger}, DIETRICH V. MICHALK§ and UWE QUERFELD*

* University Children's Hospital, Charité, Berlin, Germany
{dagger} Institute for Transplant Immunology, University of Heidelberg, Germany
{ddagger} Institute of Medical Biology and Human Genetics, University of Innsbruck, Innsbruck, Austria
§ University Children's Hospital, Cologne, Germany.

Correspondence to Dr. Uwe Querfeld, University Children's Hospital Charité, Schumann Strasse 20-21, 10117 Berlin, Germany. Phone: 49-30-2802-2077; Fax: 49-30-2802-8844; E-mail: Uwe.Querfeld{at}charite.de


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Abstract. The long-term success of renal transplantation is limited because of chronic rejection (CR), which shows histologic parallels to atherosclerosis. Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerosis, but its role in CR has not been investigated. Plasma levels of Lp(a) are determined mainly by the inherited isoform (phenotype) of apolipoprotein(a) [apo(a)] and show an inverse correlation with the molecular weight of apo(a). Apo(a) isoforms were identified in frozen sera of 327 patients who received a renal transplant during 1982 to 1992. Long-term graft survival in recipients with high molecular weight (HMW) or low molecular weight (LMW) apo(a) phenotypes were compared retrospectively. Mean (95% confidence interval) transplant survival was 12.8 yr (range, 11.9 to 13.6 yr) in patients with HMW and 11.9 yr (range, 10.8 to 13.1 yr) in patients with LMW apo(a) phenotypes (P = 0.2065). In patients who were 35 yr or younger at the time of transplantation, mean transplant survival was more than 3 yr longer in recipients with HMW apo(a) phenotypes compared with those with LMW apo(a) phenotypes (13.2 yr [range, 12.1 to 14.4 yr] versus 9.9 yr (range, 8.5 to 11.5 yr); P = 0.0156). In a Cox's proportional hazards regression model, the presence of LMW phenotypes—but not gender, immunosuppression, or HLA mismatches—in young patients was associated with a statistically significant risk of CR (P = 0.0434). These retrospective data indicate that young renal transplant recipients with LMW apo(a) phenotypes have a significantly shorter long-term graft survival, regardless of the number of HLA mismatches, gender, or immunosuppressive treatment.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Renal transplantation is the treatment of choice for end-stage renal disease, but the long-term survival of transplanted kidneys is limited because of an insidious progressive loss of allograft function, usually referred to as chronic rejection (CR). The introduction of cyclosporin A (CyA) as an immunosuppressant has led to a reduced incidence of acute rejections and a marked improvement of graft survival rates (1,2); however, the rate of long-term graft loss (percentage of grafts lost per year) has remained unchanged in patients who are treated with CyA (3). Thus, CR is regarded as the main barrier to the long-term success of renal transplantation (4).

Besides immunologic risk factors (e.g., the number of HLA mismatches) other, nonimmunologic risk factors play a major role in the progression of CR, including hypertension and hyperlipidemia (5,6). These are widely known risk factors for atherosclerosis, and the histologic lesions of CR include vascular changes, which show similarities to atherosclerotic lesions (7); therefore, CR and atherosclerosis may share identical pathways in their pathogenesis (8).

Lipoprotein(a) [Lp(a)] is an inherited independent risk factor for atherosclerosis, but its role in CR has not been studied previously. Lp(a) is a low-density lipoprotein—like particle with an additional unique protein component, apolipoprotein(a) [apo(a)]. Apo(a) occurs in multiple isoforms that can be identified by electrophoretic separation (9). The circulating levels of Lp(a) are under genetic control by the apo(a) gene: in all populations studied thus far, isoforms of low molecular weight (LMW) are associated on average with high Lp(a) blood levels, whereas isoforms of high molecular weight (HMW) present usually with low Lp(a) levels (9,10,11,12).

We hypothesized that high Lp(a) levels might be a nonimmunologic risk factor for long-term transplant survival and that the presence of LMW phenotypes should favor CR. In the present study, we identified apo(a) phenotypes of kidney graft recipients with long allograft survival times and in a retrospective analysis compared graft survival in patients with HMW and LMW phenotypes.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Patients
Frozen sera collected from kidney allograft recipients who received their transplants at the University of Heidelberg in the years 1982 to 1992 were analyzed. All patients with a minimal transplant survival time of 2 yr were included in the analysis (n = 327). The patients were treated either with a combination of prednisone and azathioprine or with a triple therapy consisting of CyA, prednisone, and azathioprine.

Apo(a) Phenotyping
In most patients (n = 246), the apo(a) phenotype was analyzed with high-resolution phenotyping with sodium dodecyl sulfate-agarose gel electrophoresis (SDS-agarose) under reducing conditions as outlined previously (13) with slight modifications. Electrophoresis was followed by immunoblotting using the monoclonal antibody 1A2 for detection of apo(a) isoforms (9).

In the remaining 81 patients, the apo(a) phenotype was determined earlier with a commercially available SDS-polyacrylamide gel electrophoresis (SDS-PAGE) system (PHAST system; Pharmacia, Freiburg, Germany) using a 4 to 15% gradient gel followed by Western blotting with a polyclonal sheep anti-apo(a) antibody (Immuno, Heidelberg, Germany). In those patients, apo(a) phenotypes were designated as suggested by Utermann et al. (9). Unfortunately, there were no more samples available from these patients to repeat the phenotyping using SDS-agarose. However, both apo(a) phenotyping methods were available in 160 patients, and we observed that the allocation of these patients to the HMW and LMW group was identical with both methods in 95% of the patients.

Data of all patients were combined for the final analysis of longterm transplant survival, and in patients in which both phenotyping methods were used, results of the more sensitive SDS-agarose were used for the allocation to the LMW and HMW groups.

Statistical Analyses
Because of the high number (>30) of detectable apo(a) isoforms with SDS-agarose, 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 kringle IV (K-IV) repeats according to the molecular weight of the smaller apo(a) isoforms to have sufficient sample sizes in each category (14). Because patients 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 (13,15,16,17,18). The LMW group included all patients with at least one apo(a) isoform with 11 to 22 K-IV repeats (or isoforms F, B, S1, S2 when analyzed with SDS-PAGE); the HMW group comprised all patients who had only isoforms with more than 22 K-IV repeats (or all isoforms >S2 with SDS-PAGE) (17,19) (Table 1). When two apo(a) isoforms were detectable, we used only the smaller apo(a) isoform for categorization, which was discussed recently in detail (16).


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  		Table 1. Apo(a) phenotypes in renal transplantation patientsa
 

For analyzing differences in transplant survival time, all patients (grouped into LMW and HMW) were included in the Kaplan-Meier analysis, and observations were censored if they were lost to follow-up or died before the day of evaluation. The significance of differences between the HMW and LMW groups was analyzed by the log-rank test. The influence of various factors on long-term transplant survival was analyzed by Cox's proportional hazards regression model.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
A total of 327 patients (211 male, 116 female) who received transplants in the years 1982 to 1992 were studied. The age of the patients at the time of transplantation ranged from 3 to 66 yr (median, 35 yr); 40 patients received a second transplant, and we could identify 111 patients with an LMW apo(a) phenotype and 216 with an HMW apo(a) phenotype (Table 1). When all patients were analyzed together, mean transplant survival time (95% confidence interval) was 12.8 yr (range, 11.9 to 13.6 yr) for patients with HMW phenotypes and 11.9 yr (range, 10.8 to 13.1 yr) for patients with LMW phenotypes; however, this difference was not statistically significant (P = 0.2065; Figure 1).



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  		Figure 1. Transplant survival analysis in all patients (n = 327). Comparison of transplant survival in patients with high molecular weight (HMW) and low molecular weight (LMW) apolipoprotein(a) [apo(a)] phenotypes was estimated by Kaplan-Meier analysis. —, patients with LMW apo(a) phenotypes; ---, patients with HMW apo(a) phenotypes.

 

Because high plasma Lp(a) levels are a risk factor for cardiovascular disease, especially in younger patients (20,21,22), we compared transplant survival after dividing the patients into two groups depending on the age at time of transplantation: patients 3 to 35 yr (n = 153; transplant survival, 12.4 yr [range, 11.4 to 13.4 yr]) and patients 36 yr and older (n = 174; transplant survival,: 12.5 yr [range, 11.6 to 13.4 yr]). Within these subgroups, there was a clear influence of LMW phenotypes on transplant survival only in the younger group (13.2 yr [range, 12.1 to 14.4 yr] in HMW and 9.9 yr [range, 8.5 to 11.5 yr] in LMW; P = 0.0156; Figure 2) but not in patients 36 yr and older (12.3 yr [range, 11.2 to 13.4 yr] in HMW and 12.9 yr [range, 11.3 to 14.5 yr] in LMW; P = 0.2065). The distribution of LMW/HMW apo(a) phenotypes was similar over the total time of observation (i.e., there were approximately 33% LMW phenotypes during 1982 to 1992) and was not different in patients who were treated with either CyA or azathioprine/prednisone (data not shown).



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  		Figure 2. Transplant survival analysis in 153 patients younger than 35 years at the time of transplantation. Comparison of transplant survival in patients with HMW and LMW apo(a) phenotypes was estimated by Kaplan-Meier analysis. —, patients with LMW apo(a) phenotypes; ---, patients with HMW apo(a) phenotypes.

 

We analyzed further the influence of immunosuppression, number of HLA mismatches, gender, second-time transplantation, age, LMW/HMW distribution, and LMW/HMW distribution within the age subgroup 35 yr or younger at time of transplantation on transplant survival by a Cox's proportional hazard model. Only the apo(a) phenotype within the age sub-group 35 yr or younger had a statistical influence in this model (Table 2), resulting in a more than twofold increase in the relative risk (hazard ratio) for transplant loss in patients with LMW apo(a) phenotypes.


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  		Table 2. Cox regression analysis for transplant survivala
 

Apo(a) phenotypes could be determined with high-resolution phenotyping in 106 of the 153 patients aged 35 yr or younger at time of transplantation. Mean transplant survival showed a decrease in patients with fewer than 22 kringle repeats (Table 3), but this difference was not statistically significant because of the small number of patients in the different subgroups (P = 0.3936).


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  		Table 3. Association of the number of kringle IV repeats and long-term renal transplant survival in patients aged 35 years or younger at time of transplantation
 


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
The present study was performed to analyze the impact of the apo(a) polymorphism on long-term renal transplant survival. Because serum lipoprotein(a) levels had not been measured in the patients and measurements from frozen sera with a long storage time frequently are inaccurate (23), we tried to estimate the impact of Lp(a) by analyzing HMW and LMW subgroups of the apo(a) phenotype. The present study shows that LMW phenotypes, which are associated with higher Lp(a) serum levels, have a detrimental effect on transplant survival. Remarkably, this effect, although present in the total study population, was statistically significant only in the patients aged 35 yr or younger at time of transplantation. This effect was independent of gender, immunosuppression, or HLA mismatches.

Possible Pathogenetic Mechanisms
CR is characterized by pronounced vascular changes. Intimal proliferation and subintimal accumulation of connective tissue are hallmarks of CR (7), and it has been proposed that endothelial activation and inflammation are the primary events that lead to progressive narrowing of arterial vessels (7). In vitro studies have provided evidence that may explain how Lp(a) could participate in vascular injury: Lp(a) promotes endothelial activation through increased intercellular adhesion molecule-1 expression (24) and proliferation of vascular smooth muscle cells by diminished secretion of active transforming growth factor-ß (25,26,27). Moreover, Lp(a) interacts with macrophages, leading to endothelial activation and invasion of the endothelium by macrophages (28,29). Prothrombotic effects by interaction of Lp(a) with plasminogen receptors (30) and inhibition of fibrinolysis (31) also may play a role. It thus is conceivable that Lp(a) could play an active role in the process of CR.

Lp(a) shows a striking association with renal disease. Elevated Lp(a) levels in plasma are found in patients with the nephrotic syndrome or nephrotic-range proteinuria regardless of renal function, with chronic renal failure regardless of cause, in patients who are treated by hemodialysis and peritoneal dialysis and after transplantation (15,18,32,33). The factors that lead to elevated Lp(a) levels have remained largely unknown, although in patients with the nephrotic syndrome, changes in Lp(a) were related to the presence of proteinuria (34,35,36). Similarly, in patients who are treated by peritoneal dialysis, protein losses were correlated with elevations in Lp(a) (18,37), suggesting that increased hepatic Lp(a) synthesis is a major contributing factor in patients with renal disease and significant protein loss. An active role of the kidney in Lp(a) catabolism is suggested by differences in Lp(a) plasma concentrations in the renal artery and vein (38) and by the apo(a) fragments in the urine (39,40). The increased Lp(a) levels in renal failure cannot be explained simply by a decrease in GFR (15,38,41), and it is unknown whether Lp(a) levels in patients with CR will increase gradually with decreasing transplant function, because long-term studies in transplanted patients with multiple measurements of Lp(a) and GFR have not been published. A prospective evaluation of Lp(a) changes in 145 patients 4 yr after transplantation, however, suggests that the relative decrease of Lp(a) is influenced by GFR (42). Recent studies have demonstrated an increase in free, unbound apo(a) in the plasma of patients with chronic renal failure (43,44), and it is possible, therefore, that free apo(a) and/or apo(a) fragments may participate in the vascular damage that is characteristic of CR.

Apo(a) Phenotype as a Surrogate for Lp(a) Concentrations
We grouped apo(a) phenotypes into HMW and LMW categories as has been done in most other studies (13,15,16,17,41,42,45,46,47,48). Although a relative increase in Lp(a) levels in hemodialysis patients is found only in patients with HMW apo(a) phenotypes (18,46,47,48), LMW phenotypes (regardless of renal function) generally are associated with much higher Lp(a) levels. Thus, such categorization, although imperfect, will group most patients with high Lp(a) levels into the LMW group and most patients with low Lp(a) levels into the HMW group. The likelihood of a correct categorization is increased further because Lp(a) decreases after transplantation mainly in patients with HMW apo(a) isoforms (42,49). Although we assume a dose-response effect of high Lp(a) levels on transplant survival over the whole range of apo(a) phenotypes, recent data suggest that Lp(a) levels that correspond to LMW apo(a) isoforms may be more variable than previously assumed (50), and, thus, it cannot be ruled out that LMW apo(a) phenotypes may promote CR independent of Lp(a) plasma levels. This is also in line with recent results from the Bruneck Study (51), which demonstrated the LMW apo(a) phenotype is one of the strongest risk predictors for advanced stenotic carotid atherosclerosis, especially when associated with high Lp(a) levels. These results are in accordance with in vitro studies (52,53,54) on the thrombogenic nature of Lp(a), which suggested that this property is defined primarily by the particle size of apo(a) and only secondarily by the Lp(a) concentration. In other words, the same Lp(a) concentrations may be associated with a markedly different risk for atherothrombosis or CR depending on the apo(a) isoform.

It is unclear why the effect of LMW apo(a) phenotypes on transplant survival was significant only in young patients. However, several clinical studies have shown that the association of high Lp(a) plasma levels with cardiovascular disease (20,21,22), stroke (55), and carotid (56) and peripheral atherosclerosis (57) may be more pronounced in younger patients. In addition, there is evidence obtained from older patients showing no significant effect of Lp(a) levels on cardiovascular disease (58).

One possible explanation is that relatively higher doses of immunosuppressives, e.g., prednisone and CyA, which frequently are necessary in the treatment of younger patients, might increase the risk for CR by promoting other nonimmunologic risk factors, e.g., dyslipidemia and hypertension. Although transplant survival was not different in younger patients compared with older patients, increased immunosuppression could act in concert with LMW apo(a) phenotypes in effecting transplant survival in this particular group of young patients.

Limitations of the Study
A limitation of our retrospective analysis of transplant survival is the lack of histologic data. We tried to circumvent this problem by selecting patients with a minimum transplant survival of 2 yr. Because most acute rejections occur within the first few months after transplantation, these patients had a very low likelihood of acute rejection and the observed graft loss, therefore, most likely was due to CR. We could not evaluate the role of other risk factors, e.g., hypertension, hyperlipidemia, or hyperhomocysteinemia, because these data were not routinely and systematically measured in these patients during follow-up.


   Conclusion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
We identified LMW apo(a) isoforms as an inherited risk factor for long-term renal transplant survival in young renal transplant recipients, especially those younger than 35 yr. LMW apo(a) phenotypes in this group of patients may be associated with vascular changes that drive chronic rejection. Further studies on the molecular mechanisms involved in this process are indicated.


   Acknowledgments
 
This study was supported by funds dedicated to scientific work at the University Children's Hospital of Cologne (D.V.M.). F.K. is supported by the Austrian Program for Advanced Research and Technology (APART) of the Austrian Academy of Science. We thank Dr. Manfred Wiesel, Prof. E. Ritz, and Prof. O. Mehls, Heidelberg, for the permission to study sera of their patients. We thank Anke Gradehand, Cologne, for expert technical assistance in the laboratory.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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Received for publication June 9, 1999. Accepted for publication October 25, 2000.




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