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Effect of deletion polymorphism of angiotensin converting enzyme gene on progression of diabetic nephropathy during inhibition of angiotensin converting enzyme: observational follow up study

^a Steno Diabetes Centre, Niels Steensens Vej 2, DK-2820 Gentofte, Denmark, ^b Institut National de la Sante et de la Recherche Medicale SC7, Paris

Correspondence to: Dr Parving.

Abstract

Objective: To evaluate the concept that an insertion/deletion polymorphism of the angiotensin converting enzyme gene predicts the therapeutic efficacy of inhibition of angiotensin converting enzyme on progression of diabetic nephropathy.
Design: Observational follow up study of patients with insulin dependent diabetes and nephropathy who had been treated with captopril for a median of 7 years (range 3-9 years).
Setting: Outpatient diabetic clinic in a tertiary referral centre.
Patients: 35 patients with insulin dependent diabetes and nephropathy were investigated during captopril treatment (median 75 mg/day (range 12.5 to 150 mg/day)) that was in many cases combined with a loop diuretic. 11 patients were homozygous for the deletion allele and 24 were heterozygous or homozygous for the insertion allele of the angiotensin converting enzyme gene.
Main outcome measures: Albuminuria, arterial blood pressure, and glomerular filtration rate according to insertion/deletion polymorphism.
Results: The two groups had comparable glomerular filtration rate, albuminuria, blood pressure, and haemoglobin A1c concentration at baseline. Captopril induced nearly the same reduction in mean blood pressure in the two groups--to 103 (SD 5) mm Hg in the group with the deletion and 102 (8) mm Hg in the group with the insertion--and in geometric mean albumin excretion--573 (antilog SE 1.3) µg/min and 470 (1.2) µg/min, respectively. The rate of decline in glomerular filtration rate (linear regression of all glomerular filtration rate measurements during antihypertensive treatment) was significantly steeper in the group homozygous for the double deletion allele than in the other group (mean 5.7 (3.7) ml/min/year and 2.6 (2.8) ml/min/year, respectively; P = 0.01). Multiple linear regression analysis showed that haemoglobin A1c concentration, albuminuria, and the double deletion genotype independently influenced the sustained rate of decline in glomerular filtration rate (R² (adjusted) = 0.51).
Conclusion: The deletion polymorphism in the angiotensin converting enzyme gene reduces the long term beneficial effect of angiotensin converting enzyme inhibition on the progression of diabetic nephropathy in patients with insulin dependent diabetes.

Introduction

Increased synthesis of angiotensin II may play a part in the initiation and progression of diabetic nephropathy by affecting haemodynamic mechanisms and promoting growth of glomerular cells.^{1 2} Angiotensin converting enzyme is of key importance in regulating systemic and glomerular circulation by converting angiotensin I into angiotensin II and inactivating bradykinin.³ Pharmacological inhibitors of angiotensin converting enzyme have a beneficial effect on the initiation and progression of diabetic nephropathy.^{4 5 6 7 8 9} However, the beneficial effect of such inhibition on the progression of diabetic nephropathy is highly variable and several so called progression promoters have been identified-- namely, albuminuria, poor glycaemic control, and systemic blood pressure.^{9 10} Recently, a deletion polymorphism in intron 16 of the angiotensin converting enzyme gene has been associated with accelerated deterioration in kidney function in patients with immunoglobulin A nephropathy.^{11 12}

We examined the concept that the deletion polymorphism of the angiotensin converting enzyme gene predicts the therapeutic efficacy of angiotensin converting enzyme inhibition on deterioration in kidney function in insulin dependent diabetic patients suffering from diabetic nephropathy.

Patients and methods

We examined the records of all patients with albuminuria attending the outpatient clinic at Steno Diabetes Centre in 1993 who had insulin dependent diabetes mellitus and diabetic nephropathy¹³ and had had their glomerular filtration rate measured during the same year. A total of 242 white patients over 18 years old were identified, and angiotensin converting enzyme genotyping was performed in 198 of them as described in detail previously.¹⁴ Subjects were classed according to the presence (I) or absence (D) of a 287 base pair insertion in intron 16 of the angiotensin converting enzyme gene; subjects who were homozygous (II) or heterozygous (ID) for the insertion were grouped together and compared with those homozygous for the deletion (DD). We studied all previously untreated patients in whom treatment with an angiotensin converting enzyme inhibitor had been started and who had had their glomerular filtration rate measured yearly for at least three years during such treatment. Thirty five patients fulfilled these criteria and all gave fully informed consent (see table 1). The experimental design was approved by the local ethics committee.

Table 1--Clinical data at baseline on 35 patients with insulin dependent diabetes and diabetic nephropathy according
to insertion (I)/deletion (D) polymorphism of angiotensin converting enzyme gene. Values are means (SD) unless
stated otherwise
----------------------------------------------------------------------------------------------------------------------
                                                                                             Mean difference
                                                                                             (95% confidence
                                                                                            interval) between
                                                        DD        II and ID                    DD and II+ID
                                                      genotype     genotypes    P value         genotypes
----------------------------------------------------------------------------------------------------------------------
No of men/women                                          9/2         14/10       0.32
Age at onset of diabetes (years)                        11 (6)       13 (7)      0.28         -3 (-8 to 2)
Duration of diabetes at onset of nephropathy (years)    17 (10)      16 (6)      0.60          1 (-4 to 7)
Serum creatinine (µmol/l)                            81 (29)      85 (30)     0.73         -4 (-28 to 20)
No of patients with retinopathy:
  Simplex                                                 2            8         0.48
  Proliferative                                           9           16         0.71
Insulin dose (IU/kg/day)                               0.6 (0.1)    0.6 (0.2)    0.52        0.0 (-0.2 to 0.1)
Body mass index (kg/m2)                         24.2 (2.5)   23.7 (3.4)    0.62        0.6 (-1.8 to 2.9)
Antihypertensive treatment during study (mg/day):
  Captopril                                             76 (23)     65 (36)      0.25         11 (-13 to 35)
  Frusemide                                            220 (210)   130 (80)      0.11         91 (-60 to 250)
  Nifedipine                                              40          40         1.00               0
No of patients taking:
  Frusemide                                               10          18         0.32
  Nifedipine                                               5           4         0.08

All physiological investigations were carried out 4 to 18 (median 15) times during 3 to 9 (8) years of angiotensin converting enzyme inhibition in the DD group and 3 to 16 (9) times during 3 to 9 (7) years of angiotensin converting enzyme inhibition in the ID/II group, respectively. Glomerular filtration rate was measured in the morning after a single injection of edetic acid labelled with chromium-51 (3.7 MBq).¹⁵

Urinary albumin concentration was determined by radioimmunoassay during the four hour clearance period and from all 24 hour urine collections made at home (about four times a year).¹⁶ Blood pressure was measured with a standard clinical mercury sphygmomanometer (cuff 25 cm x 12 cm) on the right arm.

From venous blood samples haemoglobin A1c concentration was determined by high performance liquid chromatography (DIAMAT Analyzer, Bio-Rad, Richmond, California). Serum creatinine concentration was assessed by a kinetic Jaffe method. Serum cholesterol concentrations were measured by a conventional laboratory technique. Retinopathy was assessed by fundus photography after pupillary dilatation.

STATISTICAL ANALYSIS

Values are given as means (SD), but values for urinary albumin excretion are expressed as geometric means (antilog SE) owing to the skewed distribution. Baseline data on haemoglobin A1c concentration, albuminuria, and arterial blood pressure are based on all values during the six months preceding the start of angiotensin converting enzyme inhibition. Analysis of the three above mentioned variables during angiotensin converting enzyme inhibition was based on all measurements.

The initial rate of decline in glomerular filtration rate was determined from baseline to the first examination after the start of angiotensin converting enzyme inhibition a mean of 3 months (range 3-24) later in the group with the deletion polymorphism and a mean of 6 (3-21) months later in the others. Linear regression analysis was used to assess the sustained rate of decline in glomerular filtration rate from all values of glomerular filtration rate in each patient during angiotensin converting enzyme inhibition. For normally distributed variables, including logarithmically transformed values of urinary albumin excretion, groups were compared by an unpaired Student's t test. For non-normally distributed continuous variables groups were compared by the Mann-Whitney U test. A ² test was used for comparison between groups of non-continuous variables. Multivariate regression analysis of putative progression promoters was performed with backward selection. The R² value is adjusted for the number of variables introduced into the model. A P value (two sided) of <0.05 was considered to be significant. All calculations were performed with a commercially available program, Statgraphics (Manugistics, Rockville, Massachusetts).

Results

Demographic and clinical data were comparable between patients in the two groups (table 1). The initial decline in glomerular filtration rate (ml/min/month) was more pronounced in 10 patients homozygous for the deletion polymorphism than in 19 patients homozygous or heterozygous for the insertion (mean difference 2.4 (95% confidence interval 4.6 to 0.2), P = 0.02). The initial decline in mean arterial blood pressure also tended to be larger in those with the double deletion (13 (11) v 7 (8), P = 0.10). However, no significant correlation was found between the initial drop in blood pressure and glomerular filtration rate. The mean ratio of initial and baseline albuminuria was nearly identical (0.65 (0.34 to 1.24) in those with the double deletion and 0.59 (0.40 to 0.88) in the others).

A direct correlation between the initial and the sustained decline in glomerular filtration rate was observed (r = 0.46, P = 0.01). An initial decline in glomerular filtration rate of 1 ml/min/month corresponds to an enhanced sustained glomerular filtration rate reduction of 0.57 ml/min/year (R² = 22%).

Glycaemic control, systemic blood pressure, albuminuria, and glomerular filtration rate were comparable at baseline in the two groups (table 2). Table 2 also shows the variables during angiotensin converting enzyme inhibition lasting from 3 to 9 years. Patients homozygous for the deletion tended to receive a higher dose of captopril and frusemide and a greater proportion of them were treated with nifedipine (5 (45%) v 4 (17%), respectively). The mean ratio of sustained and baseline urinary albumin values was nearly identical in all patients (0.63 (0.40 to 1.00) in 11 patients with the double deletion and 0.65 (0.40 to 1.06) in 24 patients with the insertion). The mean difference of change in haemoglobin A1c concentration between those with the double deletion and those with the insertion was 0.3 (-0.6 to 1.2), in arterial blood pressure 1(-9 to 11)/2(-3 to 7) mm Hg, albuminuria ratio 1.0 (0.5 to 1.8), and sustained decrease in glomerular filtration rate (ml/min/year) 3.1 (0.8 to 5.4). Furthermore, a multiple linear regression analysis showed that haemoglobin A1c concentration, albuminuria, and the DD genotype of the angiotensin converting enzyme gene independently influenced the sustained rate of decline in glomerular filtration rate (R² (adjusted) = 0.51). Serum cholesterol concentration remained nearly identical in the two groups during the whole study period (6.0 (1.2) and 5.9 (1.0) mmol/l).

Table 2--Changes in haemoglobin A1c concentration, arterial blood pressure, albuminuria, and glomerular filtration rate before and during long term
inhibition of angiotensin converting enzyme for diabetic nephropathy according to insertion (I)/deletion (D) polymorphism of angiotensin converting
enzyme gene. Values are means (SD) unless stated otherwise
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------
                                                  Baseline                                             Angiotensin converting enzyme inhibition
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                                             Sustained
                                                                                                                                                            decrease in
                                                                                           Glomerular                                                       glomerular
                                                             Arterial                       filtration                        Arterial                      filtration
                               Period of                     blood                             rate                            blood                           rate
                             investigation  Haemoglobin      pressure      Albuminuria       (ml/min/        Haemoglobin       pressure      Albuminuria     (ml/min/
Genotype                        (years)      A1c (%)   (mm Hg)        (µg/min)*     1.73 m2)    A1c (%)   (mm Hg)        (µg/min)*    year)
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------
DD (n = 11)                     7 (2)        9.7 (1.8)      146/94 (14/8)    908 (1.3)       100 (21)+         9.7 (1.3)      138/85 (11/5)    573 (1.3)     5.7 (3.7)++
II + ID (n = 24)                6 (2)        9.0 (1.2)      142/90 (16/9)    756 (1.2)        95 (29)+         9.5 (1.2)      137/84 (14/7)    470 (1.2)     2.6 (2.8)++
Mean difference (95%
 confidence interval) in DD                     0.7         4 (-7 to 16)/       1.2                                0.3        1 (-9 to 11)/       1.0              3.1
 and II + ID genotypes       1 (-0.3 to 3)  (-0.4 to 1.9)   4 (-3 to 10)   (0.6 to 2.3)     5 (-14 to 25)    (-0.6 to 1.2)&   2 (-3 to 7)&  (0.5 to 1.8)     (0.8 to 5.4)
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------
*Geometric mean (antilog SE) and mean ratio (95% confidence interval) indicated.
+Ten patients in DD group, 19 in ID + II group.
++ P<0.01 for DD v ID + II group.
&Mean difference between changes (95% confidence interval) in DD and II + ID genotype.

Discussion

Our longitudinal study of kidney function in patients with insulin dependent diabetes and diabetic nephropathy showed an accelerated initial and sustained loss of glomerular filtration rate during angiotensin converting enzyme inhibition in patients homozygous for the deletion polymorphism of the angiotensin converting enzyme gene. We found a direct correlation between the initial loss and the decline in glomerular filtration rate during maintenance treatment with angiotensin converting enzyme inhibitors. Finally, glycaemic control and albuminuria during the whole treatment period and the DD genotype independently influenced the sustained rate of decline in glomerular filtration rate or, in other words, acted as progression promoters.

The genotype distribution of the insertion/deletion polymorphism in the present study was similar to that found in a larger cohort¹⁴(DD, 31% v 32%; ID, 49% v 48%; and II, 20% v 20%, respectively). The method of measuring glomerular filtration rate that we used is accurate and precise,¹⁷ and we took repeated measurements over at least three years, thus fulfilling the requirements for obtaining a valid determination of the rate of decline in glomerular filtration rate.¹⁸

Originally, Yoshida et al suggested that the deletion polymorphism in the angiotensin converting enzyme gene is a risk factor for the progression of IgA nephropathy.¹¹ Recently, the data have been confirmed and extended to include various non-diabetic nephropathies.^{12 19}

The natural course of diabetic nephropathy is characterised by a progressive increase in systemic blood pressure and albuminuria and an average decline in glomerular filtration rate of 10-15 ml/min/year.^{2 20} Treatment to lower blood pressure induces a faster initial and slower subsequent decline in glomerular filtration rate in diabetic nephropathy.^{7 8 9 10 13} Our long term study found that treatment with angiotensin converting enzyme inhibitors often combined with diuretics reduces arterial blood pressure, arrests the progressive increase in albuminuria, and reduces the rate of decline in glomerular filtration rate in diabetic nephropathy; this is in agreement with previous studies.^{7 8 9 10 13} Differences in well established risk factors for progression of diabetic nephropathy, such as arterial blood pressure, glycaemic control, albuminuria, and serum cholesterol concentration,^{2 10 21} could not account for the observed difference in the sustained rate of decline in glomerular filtration rate between the patients with the double deletion and those with the insertion polymorphism. It should be recalled that patients' sex had no impact on the progression of diabetic nephropathy.²² These findings and the multiple linear regression analysis suggest that the deletion polymorphism of the angiotensin converting enzyme gene independently influences the progression of diabetic nephropathy. A possible explanation for the deleterious effect of the deletion polymorphism on kidney function may be increased angiotensin II formation²³ or resistance to long term angiotensin converting enzyme inhibition, or both. This is corroborated by the fact that the dose and the number of different antihypertensive drugs tended to be higher in the patients with the double deletion polymorphism. From a therapeutic point of view, our study suggests that patients with diabetic nephropathy who are homozygous for the D allele should be offered earlier and more aggressive antihypertensive treatment with angiotensin converting enzyme inhibitors. A better option may be angiotensin II receptor blockade combined with strict glycaemic control.

Funding: No additional funding.

Conflict of interest: None.

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