Angiotensin I-converting enzyme gene polymorphism in non-diabetic renal disease

Ola Samuelsson1, Per-Ola Attman1, Rutger Larsson1, Henrik Mulec1, Lars Rymo2, Lars Weiss1 and Anne Ricksten2

1 Department of Nephrology and 2 Laboratory Medicine, University of Göteborg, Göteborg, Sweden

Correspondence and offprint requests to: O. Samuelsson, M. D., Department of Nephrology, Sahlgrenska Sjukhuset, S-413 45 Göteborg, Sweden.



   Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene determines the concentration of ACE in serum and local tissues. The role of this polymorphism in progressive chronic renal disease is still not fully clear.

Methods. We analysed the impact of the D/D polymorphism on the rate of decline in renal function in patients with non-diabetic, chronic progressive renal insufficiency. Seventy non-diabetic patients, aged 21–69 years at baseline, with moderately advanced renal insufficiency due to primary chronic renal disease were followed for an average of 3 years with repeated measurements of their glomerular filtration rate (GFR). Their mean GFR at baseline was 41 ml/min/1.73 m2 body surface area (BSA). The polymerase chain reaction (PCR) amplification method was used to detect the I/D polymorphism of the ACE gene. GFR was measured as the clearance of 51Cr-EDTA and the individual rate of progression was calculated using linear regression.

Results. The distributions of the genotypes were: D/D 30%, I/D 49%, and I/I 21%. The rates of progression in the three ACE genotype groups were an annual decline in renal function of -4.2 (SD 4.6) ml/minx1.73 m2 BSA in the D/D group, -2.7 (SD 3.4) in the I/D group and -1.7 (SD 3.4) in the I/I group (ANOVA P=0.12). In patients with proteinuria below 3.5 g/24 h, the D/D group had a significantly higher rate of progression than patients with the I allele. The same was found in a separate analysis when only patients with normal apoliprotein B (below 155 mg/dl) levels were analysed. Furthermore, the D/D genotype was a significant predictor of a more rapid decline in renal function in male, but not female, patients.

Conclusion. The results in this study in non-diabetic patients with chronic renal disease indicate that the presence of the D allele in the ACE genotype may be of particular importance as a predictor of a high rate of progression in male patients who otherwise do not have a major burden of documented and important prognostic factors for progressive renal insufficiency.

Keywords: ACE-genotype; chronic renal insufficiency; progression



   Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Polymorphism of the angiotensin I-converting enzyme (ACE) gene was identified in 1990 [1]. The insertion/deletion (I/D) polymorphism of the ACE gene has been shown to determine the concentration of ACE in serum and in local tissues [2,3]. The pathophysiological role of this polymorphism has been discussed and it has been proposed that the DD genotype of the ACE gene may be an independent risk factor for cardiac disease [48]. Whether the I/D polymorphism plays an important role in renal disease is still controversial [9].

In diabetic nephropathy there are conflicting results regarding whether patients with the DD genotype progress in their renal insufficiency at a higher rate [1014]. In the meta-analysis of Staessen et al. [8] it was concluded that the deletion polymorphism sets the stage for renal microvascular complications. Studies in patients with IgA nephropathy have suggested that the I/D polymorphism may play a role in the progression of this particular renal disease [1520]. In three recent, but rather small, studies it was reported that the decline in renal function was also more rapid in patients with the DD genotype in other non-diabetic renal patient categories [2123]. Furthermore, it has also been discussed whether the therapeutic response to ACE-inhibition is dependent on the ACE gene polymorphism [9,15,17,21,24,25].

As pointed out in two recent reviews [9,26], a common problem in addressing the question of whether gene polymorphism plays a role in various renal diseases is the limited size of the patient samples, with consequently low statistical power. The aim of the present study was to analyse the impact of ACE gene polymorphism on the rate of progression in our prospectively followed patient series of subjects with non-diabetic renal disease.



   Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient population
The patient population consisted of 70 adult non-diabetic patients with primary chronic renal disease. They made up the majority (96%) of the study population (n=73) of a long-term, prospective observational study, the primary objective of which was to analyse the relationship between lipid abnormalities and progressive renal insufficiency [27]. The patient population has been described in detail elsewhere [26]. Of the 70 patients, 43 had chronic glomerulonephritis, 11 had chronic interstitial nephritis, eight had adult polycystic kidney disease and eight had nephrosclerosis as the underlying chronic renal disease. In the remaining three patients the renal disorder could not be diagnosed adequately. Fifty-four (77%) patients were male and 16 (23%) female. None of the patients was treated with any lipid-lowering therapy, immunosuppressive therapy or advised to follow any specified dietary regimen. At the start of the study, 64 (89%) of the patients were treated with antihypertensive therapy and 45 (63%) were receiving an ACE inhibitor. Only minor changes in the pharmacological treatment were made in very few patients during the study period.

The patients were followed with repeated visits and determination of the glomerular filtration rate (GFR). The time of follow-up ranged from 1 to 4 years with an average of 3.0 (SD 0.7) years, and the average number of GFR measurements was 9.5 (SD 3.6; range 4–17). Only two patients had fewer than five measurements during their follow-up (GFR was measured on four occasions in each).

Methods
GFR was determined as the plasma or renal clearance of 51Cr-EDTA according to established procedures [28]. Urinary protein excretion was determined using a turbidometric method [29]. At the beginning of the study venous blood samples were drawn into EDTA-containing vials and a 5-ml aliquot of blood was stored at -70°C.

All the samples were then thawed and analysed after completion of the observational study. Genomic DNA was prepared using a standard method from isolated white blood cells and analysed using the polymerase chain reaction (PCR). The primers used in the PCR detection of the ACE gene I/D polymorphism were as described previously [30]. The PCR reaction was optimized for an equal amplification of the I and D alleles. This is of importance because the D allele is amplified more efficiently than the I allele, which can result in false DD genotypes. Briefly, 5 ml (~300 ng) of genomic DNA was amplified in a 50-µl reaction containing 2 mM MgCl2, 1.25 U Taq-DNA polymerase and 20 pmol of the respective primer. The amplification reaction was performed by 30 incubation cycles of thermal denaturation at 92°C for 60 s, primer annealing at 57°C for 60 s, primer extension at 72°C for 60 s and a final extension at 72°C for 10 min. The DD homozygotes were confirmed by a PCR assay with one of the primers, 5'-GAGACGGAGTCTCGCTCTGT-3', deduced from the insertion region of the ACE gene. Further confirmation of the amplification products was obtained by hybridization with an oligonucleotide for specific sequences in the amplified region.

Statistical methods
Standard statistics were used to illustrate the salient features of the data. The individual rate of progression of renal insufficiency was calculated as the slope of GFR versus time plot (linear regression) and was expressed as the annual change in GFR (ml/min/1.73 m2 BSA per year). Analysis of variance (ANOVA) was used to describe and determine statistical inference between the three genotypes of the ACE gene, followed by pairwise comparisons.

To evaluate whether the influence of the ACE genotype increased in importance when other factors important for progression were eliminated, patients with nephrotic range proteinuria, uncontrolled blood pressure (defined as a blood pressure >160 mmHg systolic or 90 mmHg diastolic) or elevated apolipoprotein B levels (i.e. defined as a plasma concentration >155 mg/100 ml) were excluded from the analyses. These predictive factors were chosen based on our previous results in this prospective study [27]. Furthermore, to analyse whether the genotypes interacted with gender the study group was divided according to sex.



   Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The baseline patient characteristics are presented in Table 1Go. The sex distribution was the same in all three ACE genotype groups. The rate of progression of renal insufficiency was 2.6 times higher in the D/D group than in the I/I group, with the I/D group having a progression rate in between. However, the difference between the three groups did not reach statistical significance (P=0.12, ANOVA). When patients with a substantial degree of proteinuria were excluded, the DD genotype was found to have a significantly higher rate of progression than the patients with the I allele (Table 2Go). A similar pattern, although not statistically significant, was observed when patients with poor blood pressure control were excluded (data not given). Table 3Go shows the results when patients with high plasma concentrations of apolipoprotein (apo) B were excluded, and it is clear that the D allele was associated with a higher rate of progression in patients with normal plasma concentrations of apo B.


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Table 1. Patient characteristics at baseline in 70 non-diabetic patients with primary renal disease. Mean (SD)
 

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Table 2. Patient characteristics at baseline in 55 non-diabetic patients with primary renal disease and proteinuria <3.5 g/24 h. Mean (SD)
 

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Table 3. Patient characteristics at baseline in 44 non-diabetic patients with primary renal disease and apolipoprotein B <155 mg/100 ml. Mean (SD)
 
Male patients (n=54) with the D/D genotype had a significantly higher rate of progression than male patients with the I/D an I/I genotypes (Table 4Go), whereas in the smaller subgroups of female patients (n=16), the rate of decline in GFR was almost identical in the three genotype subgroups.


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Table 4. The rate of decline in GFR in male and female patients according to the ACE genotype. Mean (SD)
 


   Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The main finding of this study was that the D/D genotype of the ACE gene was associated with a higher rate of progression of renal insufficiency in non-diabetic male patients with primary chronic renal disease, who would otherwise seem to be at a rather low risk of having a rapid decline in renal function.

The patients in the present study represented the majority of the non-diabetic patients with chronic renal insufficiency who participated in our prospective study [27], the primary objective of which was to explore the possible role of renal dyslipoproteinaemia [31] in the progression of renal dysfunction. This patient group was representative of unselected adult asymptomatic subjects with moderately advanced renal insufficiency due to primary renal disease with characteristic alterations in the apolipoprotein, rather than the lipid, pattern [27,31]. All patients were monitored closely during follow-up and managed according to recommended treatment strategies. Nine out of ten patients were on active antihypertensive drug therapy with the majority receiving an ACE-inhibitor. The distributions of the three ACE genotypes were the same as reported in healthy control populations [7].

Studies in both patients with diabetic nephropathy and non-diabetic patients with other underlying renal diseases have suggested that patients with the D/D genotype in the ACE gene progress at a higher rate than those with the I allele [1220,26]. Our findings confirm the observation by van Essen et al. [21] in a patient series very similar to ours with primary chronic renal disease. In their recent meta-analysis, Staessen et al. [8] concluded that the D allele sets the stage for atherosclerotic and renal microvascular complications in hypertension and diabetes mellitus. However, the association between the D allele and a higher rate of progression in primary chronic renal disease has not been a consistent finding in all published patient series [15,32].

The outcome of the present study, with an association between the D allele and the rate of progression of renal dysfunction in our non-diabetic patients with primary renal disease, indicates that the ACE genotype is of prognostic importance in these patient categories. Furthermore, by accounting for other factors with a documented impact on the rate of progression of renal insufficiency [33,34], we observed that the presence of the D/D genotype seems to be of particular prognostic importance in patients who would otherwise be expected to be at a rather low risk of a more rapid decline in renal function. Thus, patients with low-to-moderate degrees of urinary protein excretion, normal plasma levels of apo B or with normotension had a higher rate of progression if they had the D/D genotype in comparison with the I/I genotype, with patients with the I/D genotype in between. This is in accordance with observations by Hunley et al. [16] and Stratta et al. [19] in their patients with IgA nephropathy, and with observations in patients with coronary heart disease, in which the D/D genotype was reported to be of particular importance as a risk factor for myocardial infarction in subjects considered to be at low risk according to commonly accepted coronary risk factor criteria [4].

As stated above, the rate of progression of renal insufficiency in chronic renal disease is influenced by well-established risk factors such as hypertension, hyperlipidaemia and proteinuria [33,34]. The adverse synergistic effects of proteinuria and high blood pressure have been confirmed [33]. In addition, proteinuria and elevated apo B levels have been shown to act synergistically in promoting an accelerated rate of progression [34]. The role of proteinuria in progressive renal disease has been discussed extensively over the last decade. There is recent evidence that heavy protenuria not only serves as a marker for extensive renal damage, but also can, in itself, cause renal damage and thereby directly aggravate the decline in renal function [35,36]. In patients with heavy proteinuria the effect of excess proteins filtered from glomeruli into renal tubules may be of great functional importance in initiating interstitial inflammation and tubular atrophy [36]. In this category of patients, other risk factors for progression, such as the D/D genotype of the ACE gene, may be of minor importance due to the overriding and important damaging effects of the protein load in the renal tubules.

However, patients with low to moderate proteinuria are also heterogeneous with regard to the rate of progression. The observation in our study, and in two recent studies in IgA nephropathy [16,19], that the role of the D/D genotype as a predictor of progression seems to be particularly important in patients with low to moderate proteinuria, indicates that the presence or absence of the D allele may be used to better identify patients with poor renal prognosis in this group of renal patients. Most of these patients would otherwise have been regarded as being at a rather low risk for progressive renal failure.

Many studies of the ACE gene polymorphism in chronic renal disease do not present baseline data on both proteinuria and GFR in relation to the three various genotypes. In studies in which such data are available there is no difference in the degree of proteinuria, at a similar degree of renal insufficiency, in the three ACE genotype groups [1623,32]. Thus, the D/D genotype does not seem to be directly associated with heavy proteinuria. In our study, patients with the D/D genotype even had slightly less (but non-significantly so) proteinuria than that observed in the I/D and I/I genotype groups. Most probably, the D/D genotype does not increase the susceptibility for renal disease. However, the presence of this ACE gene polymorphism may potentiate the development of further renal damage once it has occurred [19]. The mechanism(s) by which the ACE gene polymorphism contributes to an accelerated loss of renal function is yet to be clarified.

The importance of the D/D genotype as a predictor of progressive renal failure in patients who would otherwise seem to be at low risk, is an important finding and may enable us to also identify a genetic marker for progressive disease. This may be of great importance for future patient management. The interplay between different types of risk factor, genetic and others, may be one underlying reason why not all studies in primary chronic renal disease have consistently found a clear association between ACE gene polymorphism and the rate of progression of the disease. In patient series with a cluster of other well-established predictive factors for progression of renal insufficiency, the impact of the D allele may be of lesser importance and, thus, not stand out in statistical risk factor analysis. Another explanation for contradictory results of the role of gene polymorphism for the rate of progression may be purely methodological and due to small sample sizes [9]. This necessitates pooling different independent studies [9,26] and the performance of meta-analysis [37], such as that by Staessen et al. [8] in diabetic nephropathy.

Gender has been reported to have an impact on the development of renal disease. In patients with chronic renal disease, the rate of progression of renal insufficiency has been seen to be more rapid in men than in women, independent of blood pressure and plasma lipid levels [38]. It has been speculated that direct receptor-mediated effects of sex hormones may determine the susceptibility to renal damage [38]. In our patients, the D/D genotype was associated with a higher rate of progression in men, in contrast to the observation in women. Whether this finding was due to chance (the female patient group being small in our study) or to the renal protective effects of female sex hormones, which may counteract the negative effects of the ACE genotypes with the D allele, is presently speculative.

The observation that the D/D genotype of the ACE gene may be of particular prognostic importance in patients with a profile of risk factors for progression that would otherwise indicate a low risk for a rapid rate of decline in the renal function, may have important clinical implications. By determining the ACE genotype in this subgroup of patients with chronic renal disease we may be able to better identify individuals at a higher risk for progressive renal insufficiency. However, at present, we do not know which, or even whether, particular intervention strategies should be used to improve the prognosis of the renal disease in these patients. Surprisingly, intensive treatment with ACE-inhibtion does not seem to be particularly efficacious in these patients [10,21,22].

In conclusion, in this study of non-diabetic patients with chronic renal disease, the presence of the D allele in the ACE genotype was associated with a higher rate of progression of renal insufficiency. This seemed to be of particular importance in patients who did not have a major burden of other important prognostic factors for progressive renal failure.



   References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Received for publication: 13. 4.99
Accepted in revised form: 29.11.99





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