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NDT Advance Access originally published online on May 21, 2008
Nephrology Dialysis Transplantation 2008 23(10):3166-3173; doi:10.1093/ndt/gfn258
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Impact of plasminogen activator inhibitor-1 gene polymorphisms on  primary membranous nephropathy

Cheng-Hsu Chen1,3,5,6,8, Kuo-Hsiung Shu1,6, Mei-Chin Wen2,5, Kuo-Jung Chen1,6, Chi-Hung Cheng1,5,6, Jong-Da Lian6, Ming-Ju Wu1,6,7, Tung-Min Yu1 and Fuu-Jen Tsai3,4

1 Division of Nephrology, Department of Internal Medicine, 2 Department of Pathology, Taichung Veterans General Hospital 3 Institute of Clinical Medicine, China Medical University 4 Department of Medical Genetics, China Medical University Hospital 5 Department of Biotechnology, Hung Kuang University 6 Division of Nephrology, Chung Shan Medical University Hospital 7 School of Medicine, National Yang-Ming University, Taipei 8 Department of Life Science, Tunghai University, Taichung, Taiwan

Fuu-Jen Tsai, Department of Medical Genetics, China Medical University Hospital, No. 2 Yuh Der Road, Taichung, 404, Taiwan. Tel: +886-4-22052121; Fax: +886-4-22331913; E-mail: d0704{at}www.cmuh.org.tw



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Idiopathic membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in adults, and 25% of MN patients proceed to end-stage renal disease. Plasminogen activator inhibitor type 1 (PAI-1) activity plays an important role in renal fibrosis. The objective of this study was to clarify the relationship between PAI-1 gene polymorphisms and the progression of MN-associated pathologies.

Methods. We recruited a cohort of 104 biopsy-diagnosed MN patients and 142 healthy subjects that served as controls. Genotyping of PAI-1 gene polymorphisms was performed using allele-specific polymerase chain reaction methods. We then analysed associations between PAI-1 gene 4G/5G polymorphisms and clinical manifestations and progression of MN.

Results. The genotype distribution had no effect on the development of MN. The last measured creatinine clearance in MN patients having the 4G/4G genotype was significantly lower than in patients having the 4G/5G or 5G/5G genotypes (43.6 ± 33.6, 55.8 ± 44.3 and 73.3 ± 29.8 ml/min, respectively, P = 0.008). Coronary artery diseases were more prevalent in patients having the 4G5G (14/32%) and 4G4G genotypes (4/11%) than in those having the 5G5G genotype (1/5%, P = 0.008). Peripheral vascular events were more prevalent in patients having the 4G5G (18/41%) and 4G4G (6/16%) genotypes than in those having the 5G5G genotype (3/14%, P = 0.021). Disease progression occurred more frequently in patients having the 4G4G (20/53%) and 4G5G (25/57%) genotypes compared with those having the 5G5G genotype (5/23%, P = 0.026).

Conclusions. The presence of the 4G allele was associated with renal deterioration and increased cardiovascular as well as other vascular events in MN patients. These findings should prompt specific considerations for the treatment of MN in patients having the 4G4G genotype.

Keywords: cardiovascular events; gene polymorphism; malignancy; plasminogen activator inhibitor; primary membranous nephropathy



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
Idiopathic membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in adults. It is a complex multifactorial disease in which both genetic and environmental factors contribute to susceptibility and severity. Although the genetic basis of MN is not fully understood, the major histocompatibility complex (MHC) class II region has been implicated in disease susceptibility. For example, there is a close reported association between expressions of haplotypes HLA-A1, B8 and DR3 and a poor prognosis for male MN patients [1]. However, non-HLA alleles also predispose individuals towards the development of MN. For instance, renal expression of TNF-{alpha} was significantly greater in MN patients than in patients with minimal change disease, diabetes nephropathy, IgA nephropathy or other diseases [2]. In a recent report, the TNF-{alpha} gene G-308A polymorphism was found to be a risk factor for the development of MN; however, it did not impact on renal survival [3]. In other reports, no relationship has been found between severity or progression of the disease and any of the tested single genotypes [HLA-DR3, TNF-{alpha} gene G-308A, angiotensin-converting enzyme insertion/deletion (ACE I/D), angiotensin II receptor 1 (AT1R 1166A/C), angiotensinogen (AGT M235T) and NOS (ecNOS4b/a)] [3–5], and this may be due to the smaller number of patients and short observation periods.

Membranous nephropathy, a prototype of an immune-mediated glomerular disease, is characterized by abundant, nonselective proteinuria and a variable clinical course and prognosis. The renal function changes and the course of MN are more strongly correlated with the degree of tubulointerstitial damage than with the extent of the glomerular lesion [6]; however, the pathogenesis of the interstitial inflammation and fibrosis is unclear. Since plasminogens (PA) and their inhibitors play an important role in both fibrinolysis and in extracellular matrix degradation, a diminished synthesis of renal PAs and/or increased production of renal plasminogen activator inhibitor type 1 (PAI-1) may result in an imbalance in the extracellular proteolytic process, thereby leading to progression of glomerular sclerotic lesions [7]. Several experimental and clinical studies support a role for PAI-1 in the renal fibrogenic process occurring in chronic glomerulonephritis, diabetic nephropathy and in lupus nephritis [8,9]. Patients with the 4G4G genotype have the highest levels of PAI-1 activity, whereas those with the 5G5G genotype have the lowest plasma PAI-1 activity [10]. Because PAI-1 is the main inhibitor of plasminogen activation, it regulates fibrinolysis and the activation of plasmin-mediated matrix metalloproteinase. PAI-1 is not expressed in the normal human kidney but is strongly induced in various forms of kidney diseases, leading to renal fibrosis and terminal failure [11]. Therefore, we conducted the current study to characterize the 4G/5G polymorphisms of the PAI-1 gene in patients with idiopathic MN, and to determine whether these polymorphisms correlate with several clinical parameters of disease activity, treatment efficacy and long-term prognosis.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
Study population
We recruited a cohort of 104 biopsy-diagnosed idiopathic MN patients, and 142 healthy subjects that served as controls. Subjects with malignancy, chronic diseases (including infections with hepatitis B and C viruses), lupus nephritis or drug-induced secondary MN were excluded from the study. The medical records of all the patients were reviewed, and clinical information was retrieved. Patient characteristics included: demographic variables, clinical and laboratory data of the disease courses, vascular events (cardiovascular disease and peripheral vascular events) and treatment regimens as well as their responses. Creatinine clearance (CCr) (ml/min) was estimated by Cockcroft and Gault equation: CCr = (140 – age) x IBW/(SCr x 72) (x0.85 for females). Informed consent was obtained from all participating individuals. The study protocol complied with the ethical guidelines of our hospital.

The minimal follow-up duration was 1 year, except for three patients who died from pneumonia with respiratory failure (4.4 months), septic shock (5.2 months) and subdural haemorrhage with urosepsis (1.5 months), respectively. The selection of treatment modality, either supportive or aggressive with immunosuppressants, was based on the decision of the treating physician. The supportive therapy usually included diuretics, angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin II receptor blockers (ARBs), depending on patient symptoms. The immunosuppressive therapies were any of the following regimens: (1) prednisolone 1mg/kg/day alone; (2) a 6-month course of corticosteroids alternated with chlorambucil at a dose of 0.2 mg/kg/day every other month, or cyclophosphamide 1.5–2.0 mg/kg/day or (3) cyclosporine A (CyA, Neoral, Norvatis) 3–5 mg/kg/day with or without prednisolone.

Response and outcomes
Responses to therapy were defined as (1) no response, (2) partial remission: a proteinuria reduction of >50% or a final proteinuria between 0.2 and 2.0 g/day or (3) complete remission: proteinuria <0.2 g/day. The ‘progression of renal disease’ was defined as a doubling of baseline serum creatinine (Cr) values or ESRD. ESRD was defined as a patient requiring renal replacement therapy.

Renal biopsy review
Histological scoring was based on histological lesions that included glomerular lesions, tubulointerstitial lesions, glomerulosclerosis and fibrointimal lesions. Renal biopsy specimens were reviewed by a nephropathologist, who was unaware of the clinical history, renal function and PAI-1 genotype of the patients. A semiquantitative scoring system was adopted, using a scale of 0 (absent), 1 (mild: <25%) and 2 (moderate to severe: >25%) for the assessment of tubulointerstitial change and glomerular sclerosis/obsolescence under light microscopy. Staging of the disease was also determined according to electron microscopy findings.

Determination of PAI-1 4G/5G genotype
Genomic DNA was extracted from peripheral blood leukocytes of all 104 MN patients and 142 healthy controls by standard techniques. The PAI-1 4G/5G promoter genotype polymorphism was determined by polymerase chain reaction (PCR) amplification of genomic DNA from all subjects using the allele specific primers, (1) insertion 5G allele: 5'-GTC TGG ACA CGT GGG GG-3' and (2) deletion 4G allele: 5'-GTC TGG ACA CGT GGG GA-3'. Each was in combination with a common downstream primer, 5'-TGC AGC CAG CCA CGT GAT TGT CTA G-3' that gave rise to a 139 base pair DNA fragment. A control upstream primer, 5'-AAG CTT TTA CCA TGG TAA CCC CTG GT-3', was used as a positive control in the PCR [12].

The 25-µL PCR mixture contained 50 pmol allele specific primer, 50 pmol common downstream primer, 2.5 pmol control upstream primer, 1 PCR buffer, 2.0 mmol/L magnesium chloride, 0.2 mmol/L dNTPs and 1.25 U Taq polymerase. All the reagents required for PCR were purchased from Boehringer Mannheim (Mannheim, Germany). The thermal cycling conditions were 94°C for 45 s, 67°C for 45 s and 72°C for 75 s for 30 cycles. The PCR products were separated by gel electrophoresis in 2% agarose gel (GIBCO, Grand Island, NY, USA), which had been stained with ethidium bromide and viewed under ultraviolet irradiation. Each subject was classified into 4G4G, 4G5G or 5G5G according to the presence of the 139 bp PCR product generated by the allele-specific primers.

Statistical analysis
Continuous variables were expressed as means and standard deviations. Nonparametric univariate analysis was performed with the Mann–Whitney U-test for comparison of two groups and with the Kruskal–Wallis test for comparison of multiple groups. The X2-test or Fisher exact test with Yates’ correction of contingency was used to assess dichotomous variables. One-way ANOVA was performed to determine differences among groups when the data was normally distributed; when data was not normally distributed, the Kruskal–Wallis test was used. For comparison of only two groups, t-tests or Mann–Whitney U-tests were used as appropriate.

Kaplan–Meier survival analysis was used to determine renal survival and patient survival. Univariate and multivariate Cox proportional hazards modelling was used to adjust for known prognostic factors such as gender, age, histological findings, vascular events, PAI-1 gene and malignancy. A P-value of <0.05 was considered to indicate statistical significance. All analyses were performed using SPSS 10.0 (SPSS Inc., Chicago, IL).



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
PAI-1 gene polymorphisms in MN patients and normal controls
Characteristics of MN patients and normal controls are shown in Table 1. Although MN patients were older than normal controls (P < 0.001), the use of age used as a covariate to adjust the genotype in the study population by multinomial logistic regression was shown not to be different between control and MN groups. There was also no significant difference in gender, PAI-1 genotype distribution or allele frequency between the groups.


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  		Table 1 Characteristics of membranous nephropathy (MN) patients and normal controls

 
Relationship between PAI-1 gene polymorphisms and clinical features of MN
The clinical features of MN patients with three different genotypes are shown in Table 2. There was no difference in gender distribution, age of onset, duration of follow-up, body mass index, mean blood pressure (MBP), haematuria or proteinuria. The initial laboratory tests revealed no differences in baseline creatinine level (Cr), daily urinary protein excretion (DUP) or creatinine clearance (CCr). After a mean 7.2 ± 5.2 year follow-up, the last measured serum Cr levels were 1.5 ± 1.1 mg/dL in patients with the 5G5G genotype, 2.6 ± 2.4 mg/dL in patients with the 4G5G genotype and 3.9 ± 5.3 mg/dL in patients with the 4G4G genotype (P = 0.024). The CCr in MN patients with 4G/4G was significantly lower than in MN patients with 4G/5G or 5G/5G (43.6 ± 33.6, 55.8 ± 44.3 and 73.3 ± 29.8 ml/min, respectively, P = 0.008) at the last follow-up. There was no significant difference in the last measured urine protein excretions.


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  		Table 2 Comparison of clinical and biochemical manifestations in MN patients with different PAI-1 genotype distributions

 
Relationship between PAI-1 gene polymorphisms and pathological features
Because the scoring of MN required electron microscopy images of glomeruli, only 90 biopsy specimens were adequate for review and scoring by the pathologist. There were 16 glomeruli (18%) at stage I, 51 (57%) at stage II, 17 (19%) at stage III and 6 (6%) at stage IV. There were no differences in histological stage, percentage of global sclerosis, tubulointerstitial fibrosis score or fibrointimal atherosclerosis score among the three genotypes of MN patients (data not shown).

Relationship between PAI-1 gene polymorphisms and treatment outcomes
Treatment outcomes of MN patients with either supportive or aggressive immunosuppressants were not different among the three different genotype groups, except for remission of proteinuria (P = 0.022). Patients with the 5G5G genotype appeared to be more likely to attain complete resolution, whereas 4G4G and 4G5G patients were more likely to have disease progression (53% and 57%, respectively) compared with 5G5G patients (23%, P = 0.026). Although the percentage of 4G4G and 4G5G patients who developed ESRD was twice as high as that of 5G5G patients, this did not reach statistical significance. To further study the higher rates of non-remission of proteinuria in 4G4G and 4G5G patients, a stratified analysis using Mantel–Haenszel statistics revealed a high disease progression in 4G4G patients having no remission (Table 4).


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  		Table 4 Stratified analysis of remission of proteinuria during disease progression according to PAI-1 gene polymorphism

 
Ten patients developed malignancies during follow-up. These included two prostate adenocarcinomas, one cervical carcinoma and one gastric carcinoma in 4G4G patients (11%); one squamous cell carcinoma of the skull, one basal cell carcinoma of skin, one malignant lymphoma, one adenocarcinoma of the lung and one renal cell carcinoma in 4G5G patients (11%); and one case of angioimmunoblastic T-cell lymphoma in a 5G5G patient (5%) (Table 3). There was no difference in the prevalence of malignancy among the three subgroups.


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  		Table 3 Comparison of outcomes in MN patients with different PAI-1 genotype distributions

 
Relationship between pathological features and clinical outcomes
When pathological features were correlated with treatment outcomes, we found that tubulointerstitial fibrosis and intimal fibroplasia of vessels were correlated with remission of proteinuria (Table 5). In contrast, histological scores, global sclerosis and tubulointerstitial fibrosis were correlated with disease progression (P = 0.008, 0.007 and 0.032, respectively, Table 5). Specifically, all patients with stage 4 disease, having >25% tubulointerstitial fibrosis or >25% intimal fibroplasias of vessels, developed chronic renal failure during follow-up.


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  		Table 5 Comparison of outcomes and pathological features

 
Survival analysis of MN patients with different PAI-1 genotypes
Figure 1A shows Kaplan–Meier curves for renal survival according to PAI-1 genotype distributions. Although there was a trend towards better renal survival in 5G5G patients, this difference was not significant. Figure 1B shows Kaplan–Meier curves for patient survival, and these data also showed no significant difference between the groups. There were 11 mortalities, including 3 pneumonia cases with respiratory failure, 1 septic shock and 1 acute myocardial infarction in the 4G4G group; 1 subdural haemorrhage, 1 urosepsis, 1 acute cholecystitis with septic shock, 1 B-cell lymphoma with pulmonary haemorrhage after chemotherapy and 1 bilateral psoas muscle abscess in the 4G5G group and 1 angioimmunoblastic T-cell lymphoma with septic shock after chemotherapy in the 5G5G group.


Figure 1
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  		Fig. 1 (A) Analysis of renal survival according to PAI-1 genotype 4G/5G polymorphisms in 104 patients with MN. (B) Analysis of patient survival according to PAI-1 genotype 4G/5G polymorphisms in 104 patients with MN.

 
A multivariable Cox regression analysis was used to evaluate factors that predicted renal failure and mortality. Included in this model were factors that were significant (P < 0.05) upon univariate analysis, which were gender, MBP, initial Cr level and remission of proteinuria in the renal survival analysis, and age at biopsy, BMI and malignancy in the patient survival analysis. In these analyses, initial Cr levels were adjusted in three genotype groups. Of these variables, initial Cr (HR = 3.74, 95% CI 2.11 – 6.62, P < 0.000) and remission of proteinuria (HR = 0.39, 95% CI 0.21–0.72, P = 0.002) reached significance in the renal survival analysis. These variables were age at biopsy (HR = 1.10; 95% CI 1.02–1.19, P = 0.008) and malignancy (HR = 4.64; 95% CI 0.94–22.80, P = 0.059) in the patient survival analysis. PAI-1 genotype polymorphisms were not retained in this model.

Vascular events in MN patients with different PAI-1 genotypes
The prevalence of coronary artery diseases was significantly higher in patients with the 4G5G genotype (14/32%) than in patients with the 4G4G (4/11%) and 5G5G genotypes (1/5%) (P = 0.008). A higher prevalence of peripheral vascular events was also found in patients with the 4G5G (18/41%) and 4G4G genotypes (6/16%) than in patients with the 5G5G genotype (3/14%) (P = 0.021) (Table 7). Patients carrying the 4G allele (including 4G5G and 4G4G) showed a trend towards developing coronary artery events (P = 0.061) and other peripheral vascular events (P = 0.062) compared with patients carrying the 5G allele.


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  		Table 7 Vascular events in MN patients according to PAI-1 genotype distribution

 


   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
The current study showed that the PAI-1 gene polymorphism was not correlated with the development of MN. However, we clearly demonstrated that the presence of the 4G allele in MN patients was associated with disease progression, and possibly with the occurrence of coronary artery and peripheral vascular events. Interestingly, the initial pathological features and the mode of treatments were not significantly different among the three genotypes. Even the follow-up duration was not different among these groups. These data strongly suggest a devastating role for the 4G allele in MN patients. Although renal survival and patient survival rates were not significantly different, a trend towards improved survival was found in patients with the 5G5G genotype. Because MN is an insidious disease with a protracted clinical course, it is possible that the follow-up duration in the current study was too short to detect a meaningful difference in survival among the three subgroups.

The exact mechanism by which the 4G allele exerts its detrimental effect is not fully understood. Individuals with the 4G4G genotype produce the highest serum levels of PAI-1, whereas those with the 5G5G genotype produce the lowest [10]. Individuals carrying 4G alleles have an increased risk of thrombosis, acute myocardial infarction and possibly sudden cardiac death compared to those homozygous for 5G [13]. In the presence of the 5G allele, an additional binding site is created which produces an inhibitor of PAI-1 gene transcription, leading to an attenuated level of transcription [10]. Thus, the presence of the 4G allele is associated with higher transcriptional activity, resulting in higher PAI-1 levels and activity compared with the presence of the 5G allele, whereas the heterozygous genotype is associated with intermediate levels [13,14]. Patients carrying the 4G allele produced six times more mRNA for PAI-1 in response to interleukin-1 stimulation compared to patients carrying the 5G allele [15]. PAI-1 is strongly expressed in various forms of renal disease, and it may play an important role in disease activity and progression. In addition, PAI-1 has been associated with accumulation of extracellular matrix (ECM), glomerulosclerosis and tubulointerstitial fibrosis. Krag and colleagues [16] recently reported in an animal model that a gene deficiency in PAI-1 attenuated TGF-β1-induced kidney disease to cause a decrease in both glomerular and interstitial ECM deposition. They concluded that PAI-1 mediated some of the biological effects of TGF-β1 in vivo, although they could not demonstrate that the effect was mediated through increased protease activity [16]. However, Wang and colleagues [17] found that Chinese patients with systemic lupus erythematosus having the 4G4G genotype had significantly heavier proteinuria and higher activity index than those having the 4G5G or 5G5G genotypes. They were not able to find a correlation between PAI-1 gene polymorphisms and chronicity of lupus nephritis [17]. Several other reports have indicated that PAI-1 polymorphisms may play a role in the progression of IgA nephropathy and diabetic nephropathy [18,19].

In our study, we found a correlation between the 4G allele and disease progression. The stratified analysis using the Mantel–Haenszel statistic revealed a high disease progression in 4G4G genotype patients that had no remission of proteinuria (Table 4). Indeed, we also found that the degree of glomerulosclerosis and interstitial fibrosis correlated with renal function deterioration (Table 5). We postulate that MN patients carrying that 4G allele may produce more PAI-1 locally in the kidney, leading to glomerulosclerosis and interstitial fibrosis more rapidly than in patients carrying the 5G allele. Unfortunately, we could not confirm this possibility, because we did not measure serum PAI-1 levels in our patients and did not perform follow-up renal biopsy.

The treatment strategies for patients with MN have been a subject of controversy. In our series, most of the patients were treated with ACEIs or ARBs. Despite the similar mode of treatment given to our patients, more disease progression was found in the 4G4G subgroup than in subgroups with other genotypes. These data suggest that more specific drugs that target PAI-1 synthesis could be given in addition to regular immunosuppressive regimens, especially in patients with the 4G4G genotype.

We also found an increased occurrence of cardiovascular events and other vascular events in MN patients carrying the 4G allele (Table 6). Whether this was due to the presence of more patients with chronic renal failure in this subgroup is not known since renal failure per se is a well-known risk factor for cardiovascular events. Nevertheless, others have reported that an increased prevalence of macroangiopathy was associated with the 4G4G genotype in diabetes patients [20]. In addition, the presence of the 4G allele has been associated with an increased risk for thrombosis, acute myocardial infarction and possibly cardiac sudden death [13]. Given these clinical reports, we postulate that similar vascular events might occur in the kidneys of MN patients having the 4G allele. In the long run, these vascular events may lead to renal ischaemia and further aggravate renal function deterioration. Drugs that counteract thrombosis may prove to be beneficial both in retarding renal failure and preventing vascular events in patients carrying the 4G allele.


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  		Table 6 Multivariate survival analysis for Cox proportional hazards model in renal survival and mortality

 
In conclusion, we demonstrated that the presence of the 4G allele was associated with renal deterioration as well as increased cardiovascular and other vascular events in MN patients. These findings should prompt specific considerations for the treatment of MN patients having the 4G4G genotype.



   Acknowledgments
 
We acknowledge the excellent technical assistance of Ms Yu-An Sheu and the assistance of Ms Ja-Fung Hong, Ms Der-Cheng Cheng and Ms Seng-Huei Lee with DNA extraction. K.H. Shu is a recipient of grant (TCVGH-903604C) from Taichung Veterans General Hospital. The authors are grateful to the Biostatistics Task Force of Taichung Veterans General Hospital for their assistance in statistical analysis.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 30. 8.07
Accepted in revised form: 15. 4.08


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