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*
Médecine B, Centre Hospitalier
Universitaire, Angers, Paris, France.
Laboratoire de Biochimie B, Centre Hospitalier Universitaire, Angers,
Paris, France.
Service d'informatique Médicale,
Hôpital Broussais, Paris, France.
§
Institut National de la Recherche Médicale
(INSERM U367), Paris, France.
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Diabétologie, Endocrinologie,
Hôpital Bichat, Paris, France.
Correspondence to Dr. Michel Marre, Endocrinologie, Hôpital Bichat, 46 rue Henri Huchard, 75877 Paris Cedex 18, France. Phone: 33-0-140-257-301; Fax: 33-0-140-258-842; E-mail: michel.marre{at}bch.ap-hop-paris.fr
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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150 µmol/L), and terminal (renal replacement therapy). The main end
point was the occurrence of a renal event defined as the progression to a
higher stage of diabetic nephropathy. At baseline, 251 (81%) patients had no
nephropathy, 35 (11%) had incipient nephropathy, 18 (6%) had established
nephropathy, and 6 (2%) had advanced nephropathy. The ACE I/D and M235T AGT
polymorphisms were in Hardy-Weinberg equilibrium in the patients. The median
duration of follow-up was 6 yr (range, 2 to 9 yr). The occurrence of renal
events was significantly influenced by ACE genotype (log-rank II
versus ID versus DD, P < 0.03) with a dominant
deleterious effect of the D allele: ID or DD versus II (adjusted
hazard ratio, 5.0; 95% confidence interval, 1.5 to 16.6). Other contributors
were high glycohemoglobin and systolic BP. In the patients who initially were
free of nephropathy, baseline plasma ACE concentration was higher in patients
who progressed to microalbuminuria (571 ± 231 versus 466
± 181 µg/L; P = 0.0032); the D allele independently favored
the occurrence of incipient nephropathy (adjusted hazard ratio, 4.5; 95%
confidence interval, 1.1 to 19.4); other contributors were male gender,
baseline systolic BP, and urinary albumin excretion. The AGT M235T
polymorphism was not associated with renal events. The D allele of the ACE I/D
polymorphism is an independent risk factor for both the onset and the
progression of diabetic nephropathy in type 1 diabetes mellitus patients. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The angiotensin I converting enzyme (ACE) was one of the first candidate genes studied in diabetic nephropathy for several reasons. First, angiotensin II, the final product of the renin-angiotensin system, increases intraglomerular pressure (7), resulting in glomerulosclerosis. Second, the glomerular pressure disequilibrium observed in diabetic rats is corrected by ACE inhibition (8), and this treatment prevents (9) diabetic nephropathy or reduces its progression in type 1 diabetes mellitus patients (10). Third, ACE levels are thought to play a critical role in determining intrarenal angiotensin and kinin concentrations (11). The ACE levels have been shown to be genetically controlled (12). An insertion/deletion (I/D) polymorphism in intron 16 of the ACE gene accounts for a large portion of the interindividual variation in ACE level (13). ACE levels are very stable within individuals (14).
We previously suggested that type 1 diabetes mellitus patients homozygous for the insertion (II genotype), who have the lowest ACE levels, have a lower risk of diabetic nephropathy (15,16). This proposal was supported by several meta-analyses (17,18,19). However, cross-sectional studies may be hampered by selection procedures and survival bias and should be confirmed by follow-up studies. Specifically, diabetic nephropathy increases by a factor of 10 the risk of cardiovascular events in type 1 diabetes mellitus (20), the major cause of premature death in type 1 diabetes mellitus patients with nephropathy (21).
Two retrospective longitudinal studies investigated the relationship between the ACE gene I/D polymorphism and diabetic nephropathy in type 1 diabetes mellitus (22,23). Small changes in urinary albumin excretion (UAE) in response to ACE inhibitor treatment were found to be related to ACE genotype in the EUCLID trial (24). However, no prospective follow-up study was carried out to identify genetic risk factors for diabetic nephropathy and to establish the role of the ACE gene. Here, we report a prospective, observational, follow-up study of the changes in kidney function of type 1 diabetes mellitus patients according to ACE genotype: the ACE D allele was associated with an increased risk for both the onset and the progression of diabetic nephropathy.
We also tested a potential role for the M235T substitution polymorphism of angiotensinogen (AGT) on the risk for diabetic nephropathy, as we reported an interaction between ACE I/D and M235T AGT polymorphisms for risk of diabetic nephropathy (16). We found no risk for diabetic nephropathy associated with M235T AGT polymorphism.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The study involved outpatient visits scheduled every 4 to 6 mo for the
measurement of weight, BP, glycohemoglobin (HbA1c), plasma creatinine, and
UAE, and yearly fundoscopy. Standardized treatment strategies were based on
local recommendations (intensified insulin treatment, target BP <140/90
mmHg (27), and use of ACE
inhibitors in diabetic nephropathy from the incipient stage
(27)). Nephropathy was
classified based on a classification derived from the one proposed by Mogensen
et al.
(1,16):
absent if UAE was normal, in absence of hypertension; incipient if UAE was in
the microalbuminuria range, without permanent hypertension; established if
there was proteinuria, with plasma creatinine concentration <150 µmol/L;
and advanced if plasma creatinine concentration was 150 µmol/L. During
follow-up, patients were scored as having end-stage renal disease (ESRD) when
renal replacement therapy was started. Major cardiovascular events (myocardial
infarction, stroke, lower limb amputation) and death were noted from hospital
records. All patients gave informed written consent; the study protocol was
approved by the local ethics committee.
Determinations
Diabetic retinopathy was classified as absent, background,
preproliferative, or proliferative
(28). UAE was measured by
nephelometry (29) (assay
sensitivity, 2 mg/L; intra- and interassay coefficient of variation, 2 and 4%,
respectively) on urine samples collected at each visit, after the elimination
of hematuria and infection. If UAE was 20 to 200 mg/L two to three times on
three consecutive visits, then persistent microalbuminuria was diagnosed
(30); if it was >200 mg/L
two to three times in the same conditions, then clinical proteinuria was
diagnosed. Systolic and diastolic BP (SBP/DBP) were measured with an automatic
device (tensiometre BP-8800, CoElectronics Co, Ltd., Komaki City, Japan) five
times at 2-min intervals while patients were supine, and mean values were
recorded. Plasma creatinine concentration was determined using the Jaffe
reaction (31), and HbA1c was
determined by HPLC (range of normal values, 4.5 to 6.2%)
(32).
ACE I/D and AGT M235T genotypes were determined as described previously (16). Plasma ACE concentration was determined by an enzyme-linked immunosorbent assay method (25).
Statistical Analyses
All data were stored and analyzed with PC-STATVIEW V (SAS Institute Inc.,
Cary, NC). Data are presented as means ± 1 SD or as medians (ranges) if
distributions were skewed. Groups were compared using the 
2
test for discrete variables and parametric (if normally distributed [ANOVA or
t test]) or nonparametric tests (if not normally distributed
[Mann-Whitney U test or Kruskal-Wallis]) for continuous variables. A
receiver operating curve was constructed to search for a threshold of baseline
ACE on the risk of occurrence of microalbuminuria in the patients who did not
have nephropathy at baseline.
The primary aim was to determine the prognostic value of ACE I/D polymorphism for the onset and progression of renal complications in type 1 diabetes mellitus. Survival analysis was performed with progression to a higher stage of diabetic nephropathy, defining a renal event as the outcome variable. Time-to-first-renal-event curves were generated by Kaplan-Meier estimation and compared using the logrank test. Cox's proportional hazards model was used to investigate the relationship between several candidate prognostic variables and the outcome variable. HbA1c was forced into the model, even if not significant in univariate analysis.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2 = 0.02; P = 0.89). The median follow-up was 6 yr
(range, 2 to 9), and it was similar for any nephropathy stages. Eight patients
(2.6%) died during follow-up: two with the ACE II genotype (one due to
ketoacidosis and one due to pancreatic malignancy), one with the ID genotype
(breast cancer), and five with the DD genotype (two ESRD, two ischemic heart
disease, and one lower limb arteriopathy) (2 = 4.342,
P = 0.11 for the genotype effect). HbA1c level was lower during
follow-up than at baseline (P < 0.0001), probably because many
patients (94 of 145 [65%]) shifted from conventional (one to two daily insulin
injections) to intensified insulin treatment (three or more daily injections
or insulin pump). The SBP/DBP of patients with established nephropathy was
lower during follow-up than at baseline (P = 0.1589/0.0022). However,
HbA1c, SBP, and DBP values measured during follow-up were highly correlated
with the baseline values within individuals (r2 = 0.92, 0.79, and
0.81, respectively).
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Fifty-two patients progressed to a higher stage of nephropathy: 39 of 251 (15.5%) without nephropathy to incipient (n = 37), established (n = 1), or advanced (n = 1) nephropathy; 4 of 35 (11.4%) from incipient to established (n = 3) or advanced (n = 1) nephropathy; 6 of 18 (33.3%) from established to advanced nephropathy (n = 4) or ESRD (n = 2); 3 of 6 (50%) from advanced nephropathy to ESRD. The characteristics of these 52 patients are given in Table 2. Both their baseline and follow-up SBP/DBP were higher than those of the other patients, but their HbA1c level was not. Only 3 of the 54 patients with genotype II progressed in nephropathy versus 33 of 150 with the ID and 16 of 106 with the DD genotypes (log-rank II versus ID versus DD, 7.26 [P = 0.0265]; II versus ID or DD, 5.42 [P = 0.0199]). There was no difference between patients with the ID and DD genotypes (log-rank, 1.61; P = 0.2051). The Kaplan Meier curve is shown in Figure 1. The cumulative incidence of renal events was 3.1 events per 100 patient-years (95% confidence interval [CI], 2.3 to 4.0): 1.0 renal event per 100 patient-years (95% CI, 0 to 2.2) in patients with the II genotype, versus 4.2 per 100 patient-years (95% CI, 2.8 to 5.6) in those with the ID and 2.8 per 100 patient-years (95% CI, 1.5 to 4.2) in those with the DD genotypes.
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The distribution of AGT M235T genotypes was in Hardy-Weinberg equilibrium at baseline (MM, 30%; MT, 49%; TT, 21%). No relationship was found between the AGT M235 T polymorphism and the risk of renal event in the whole population or in the subgroup of patients with the D allele of the ACE gene (log-rank, 4.085 [P = 0.1297]; log-rank, 3.462 [P = 0.1769], respectively).
After adjustment for other prognostic factors (gender, HbA1c during follow-up, SBP, diabetes duration, and nephropathy stage at baseline), the risk of progression in nephropathy of type 1 diabetes mellitus patients was five times higher for those with at least one D allele than for those homozygous for the I allele (adjusted hazard ratio, 5.00; 95% CI, 1.51 to 16.57). Mean HbA1c levels during follow-up and baseline SBP were also independent contributors (Table 3). Introducing age at diabetes onset or age at study inclusion did not alter the strength of the association between the risk of renal event and the ACE genotype.
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The occurrence of a renal event was significantly different in patients with the II genotype versus those with the ID/DD genotype in the subgroup of 286 patients who did not have proteinuria at baseline (log-rank, 5.326; P = 0.0210). In the 24 patients with baseline-established or advanced nephropathy, the difference was not statistically significant (log-rank, 0.314; P = 0.557). However, the incidence of renal events was twice as high in the patients with the ID/DD versus the II genotype (7.84 versus 4.35 events per 100 patient-year follow-up).
We compared patients with good glycemic control (HbA1c during follow-up,
< median, i.e., 8.5%) and poor glycemic control (HbA1c during
follow-up, median). Mean HbA1c in patients with good glycemic control was
7.7 ± 0.6% and 9.6 ± 1.0% in patients with poor glycemic
control. The cumulative incidence of renal events was 1.1 per 100
patient-years (95% CI, 0 to 2.7) for patients with the II genotype and good
glycemic control versus 2.7 per 100 patient-years (95% CI, 1.5 to
3.8) in those with genotype ID or DD and good glycemic control. It was 0.9 per
100 patient-years (95% CI, 0 to 2.5) in patients with the II genotype and poor
glycemic control versus 4.6 per 100 patient-years (95% CI, 3.0 to
6.2) in those with genotype ID or DD and poor glycemic control. All 59
participants with incipient to advanced nephropathy at baseline were given ACE
inhibitors on an intention-to-treat basis
(27). Of the 8 subjects with
the II genotype, 1 progressed to a higher stage of nephropathy during
follow-up versus 12 of the 51 subjects with the ID or DD genotypes
(not significant).
Figure 2 shows the hazard rate in patients who did not have nephropathy at baseline. Only 2 of 46 patients (4.3%) with the II genotype developed incipient nephropathy versus 22 of 116 (19.0%) with ID, and 15 of 89 (16.9%) with DD genotypes (log-rank II versus ID or DD, 4.647; P = 0.0311). There was no difference between patients with the ID and DD genotypes (log-rank = 0.065; P = 0.7993). The cumulative incidence of renal events was 2.9 per 100 patient-years (95% CI, 2.0 to 3.7): 0.8 per 100 patient-years (95% CI, 0 to 1.9) for patients with the II genotype versus 3.4 per 100 patient-years (95% CI, 2.0 to 4.8) for those with the ID and 3.2 per 100 patient-years (95% CI, 1.6 to 4.8) for those the DD genotypes. The rate of 5-yr event-free survival was 93 ± 5% in patients with the II genotype versus 85 ± 3% in patients with the ID or DD genotype. After adjustment for other prognostic factors (gender, mean HbA1c during follow-up, SBP, diabetes duration, and UAE), the risk for onset of nephropathy of type 1 diabetes mellitus patients was 4.5 times higher (adjusted hazard ratio, 4.50; 95% CI, 1.05 to 19.37) in those with at least one D allele than in those homozygous for the I allele (Table 4).
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In this subgroup of patients, who were free of nephropathy at baseline and not treated with ACE inhibitors, plasma ACE concentration was lower in the patients with the II genotype, intermediate in the patients with the ID, and higher in the patients with the DD genotype (358 ± 129, 476 ± 159, and 558 ± 226 µg/L, respectively; P < 0.0001). ACE concentration was higher in patients who progressed to microalbuminuria than in the others (571 ± 231 versus 466 ± 181 µg/L; P = 0.0032). The Kaplan-Meier renal-event survival was significantly different according to the quartile of baseline ACE concentration, with 5 events in the each first and second quartiles compared with 10 and 14 events in the third and fourth quartiles (log-rank, 8.155; P = 0.0429). The receiver operating curve of baseline plasma ACE is represented in Figure 3. The threshold of ACE concentration that best predicted the further occurrence of microalbuminuria was 488 µg/L (specificity, 60%; sensitivity, 71%; reliability, 61%).
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During follow-up, 24 cardiovascular events occurred in 18 patients: 8 myocardial infarctions (2 in patients with the II, 5 with the ID, and 1 with the DD genotypes), 5 strokes (0 in patients with the II, 3 with the ID, and 2 with the DD genotypes), and 11 lower limb amputations (1 in a patient with the II, 5 with the ID, and 5 with the DD genotypes). The occurrence of a cardiovascular event correlated with the stage of diabetic nephropathy at baseline examination (X2 = 58.8; P < 0.0001) but not with ACE I/D genotype. The relative risk of a cardiovascular event was 9.4 (95% CI, 4.1 to 21.4) in patients with baseline-established or advanced diabetic nephropathy compared with those with no or incipient nephropathy.
At baseline, 34 patients had proliferative retinopathy. During follow-up, 43 of 187 patients without retinopathy developed background retinopathy or more, 14 of 48 patients with background retinopathy at baseline progressed to preproliferative (n = 10) or proliferative (n = 4) retinopathy, and 10 of 41 patients with preproliferative progressed to proliferative retinopathy. In the 67 patients who progressed in retinopathy, follow-up HbA1c was higher than that in the other patients (9.0 ± 1.3% versus 8.5 ± 1.2%; P = 0.0012). There was no relationship between retinopathy and ACE I/D or AGT M235T genotypes (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Few patients were lost to follow-up, so this did not affect our results. The rate of progression of renal involvement in our study was similar to that in previous follow-up studies (36) and large clinical trials such as the Diabetes Control and Complications Trial (37,38). The progression promoters previously identified were also independent contributors in our study: baseline BP (36,39), glycemic control (22,38), or UAE (22,36,40). The degree of glycemic control had a similar effect to that reported elsewhere (38,41), as shown by the fact that HbA1c levels accounting for the progression of diabetic retinopathy did so to a similar extent of that reported in previous studies (41).
The ACE I/D polymorphism affected nephropathy onset and progression independent of BP and UAE, as shown by the multivariate analysis. It is unclear whether ACE gene polymorphism is associated with BP in background populations (18,42). This study was not designed to answer this question, but it suggests that the role of ACE in renal involvement is independent of its role in BP in type 1 diabetes mellitus patients.
Death and cardiovascular events were recorded and were not related to ACE gene I/D polymorphism, eliminating some survival bias. We found no association between cardiovascular events and ACE I/D polymorphism, but our study was not designed for this purpose, and the absolute number of cardiovascular events was small. However, the relative risk of cardiovascular events conferred by diabetic nephropathy was as high in our population as in other prospective reports (20).
Two longitudinal observational studies have dealt with diabetic nephropathy and ACE I/D polymorphism in type 1 diabetes mellitus (22,23). They were retrospective and the death rate was not estimated prospectively. Powrie et al. (22) examined the relationship between the development of microalbuminuria and glycemic control, with ACE I/D genotype as a secondary end point. Data concerning ACE I/D genotype were available for only 97 of the original 172 patients, making selection bias possible and reducing study power. Parving et al. (23) pointed out that GFR decreased more rapidly in proteinuric type 1 diabetes mellitus patients with the DD genotype than in the other patients, but they did not analyze the patients with the II genotype separately from those with the ID genotype to test for a dominant or codominant effect of the D allele. In a substudy of the EUCLID trial, the albumin excretion rate of type 1 diabetes mellitus patients with the II genotype increased more rapidly than that of patients with the DD genotype, whereas the response to ACE inhibitor (lisinopril) was greater in patients with the II than in those with the DD genotype (24). However, predominantly normoalbuminuric patients were studied, and there was no difference in progression from normo- to microalbuminuria or regression from micro- to normoalbuminuria (24). Thus, the clinical significance of this observation is unclear. Finally, a Finnish study reported on the follow-up of type 2 diabetes mellitus patients according to ACE I/D polymorphism. The number of patients was small, but the decline in glomerular filtration rates was least in those patients with the II genotype (43). In the present observational study, we could not find a difference for the progression of diabetic nephropathy of the patients who were receiving ACE inhibitors according to their ACE genotypes. However, this study was not designed for this purpose.
Our data were obtained in type 1 diabetes mellitus patients. The prognostic value of the ACE I/D polymorphism in type 2 diabetes mellitus is unclear (17,19,44). However, proteinuria in type 2 diabetes mellitus is conditioned by several factors, including essential hypertension, obesity, dyslipidemia, and poor glycemic control. Thus, the interaction between poor glycemic control and ACE I/D polymorphism (16,25) may have a lesser impact on renal prognosis in type 2 than in type 1 diabetes mellitus.
This and previous studies (15,25,35) suggest that the ACE gene acts like a susceptibility gene in response to uncontrolled type 1 diabetes mellitus. This is consistent with observations made in other types of renal disease: the slope of GFR decline is steeper in patients with the DD versus the II genotypes in patients affected by IgA nephropathy (45,46), and graft survival after kidney transplantation is better in genotype II patients (47).
Although the present study was prospective and longitudinal, that the type 1 diabetes mellitus patients with the II genotype displayed a better renal prognosis than the other patient does not make the ACE II genotype a cause for reduced risk of nephropathy for type 1 diabetes mellitus patients (48). An indirect argument for causality against association is provided by measurements of the intermediate phenotype (49), i.e., the plasma ACE levels. Several studies other than observational studies are mandatory to avoid refutation of a causal role for ACE in the development and progression of diabetic nephropathy, e.g., manipulation of ACE gene expression in experimental studies (49).
The practical implications of the effect of ACE I/D polymorphism on the renal prognosis of type 1 diabetes mellitus patients remain inconclusive. The protection against diabetic nephropathy in type 1 diabetes mellitus of genotype II is not absolute. No treatment strategy (especially with ACE inhibitors) has been established for the prevention and treatment of diabetic nephropathy, according to ACE I/D polymorphism (23,24). However, these findings indicate that the ACE gene I/D polymorphism is a valuable prognostic factor of the risk for the onset and development of renal complications in type 1 diabetes mellitus patients.
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Acknowledgments |
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This study was supported by the Association Diabete Risque Vasculaire, Paris, France.
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