Impact of low-dose acetylsalicylic acid on kidney function in type 2 diabetic patients with elevated urinary albumin excretion rate

Peter Gæde, Henrik Post Hansen, Hans-Henrik Parving and Oluf Pedersen

Steno Diabetes Center, Gentofte, Copenhagen, Denmark



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Low-dose treatment with acetylsalicylic acid (ASA) is widely recommended to type 2 diabetic patients as primary prevention against cardiovascular disease. High-dose treatment with cyclooxygenase inhibitors reduces urinary albumin excretion rate (AER) in type 1 diabetic patients with micro- or macroalbuminuria. Whether a similar effect on AER exists during low-dose ASA treatment, which may confound the diagnosis and monitoring of micro- and macroalbuminuria in type 2 diabetic patients, remains to be elucidated.

Methods. In a randomized, double-blind, crossover trial, 31 type 2 diabetic patients with elevated levels of AER (>30 mg/24 h) were, in random order, given ASA (150 mg/day) for 4 weeks followed by placebo for 4 weeks with a 2 week washout period or vice versa. At the end of each treatment period AER, glomerular filtration rate (GFR), blood pressure (BP), transcapillary escape rate (TERalb) of albumin and haemoglobin A1c (HbA1c) were measured.

Results. The following variables remained unchanged (mean (95% CI) unless otherwise noted) (ASA vs placebo, paired Student's t-test): AER (201 (119–341) vs 205 (124–340) mg/24 h (geometric mean, 95% CI); P=0.78), GFR (103 (94–111) vs 102 (93–110) ml/min; P=0.58), systolic BP (151 (146–158) vs 152 (146–158) mmHg; P=0.68), diastolic BP (87 (83–91) vs 87 (82–91) mmHg; P=0.88), TERalb (6.3 (5.7–6.9) vs 5.9 (5.1–6.7); P=0.45) and HbA1c (8.6 (8.1–9.0) vs 8.5 (8.1–9.0) %; P=0.60).

Conclusions. Low-dose treatment with 150 mg ASA daily does not have any impact on AER or GFR in type 2 diabetic patients with micro- or macroalbuminuria. Consequently, the widely recommended prescription of low-dose ASA as a primary and secondary prevention strategy against cardiovascular disease in these patients does not confound the diagnosis or monitoring of micro- or macroalbuminuria.

Keywords: acetylsalicylic acid; albuminuria; glomerular filtration rate; randomized trial; type 2 diabetes mellitus; urinary albumin excretion rate



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Treatment with low-dose acetylsalicylic acid (ASA) offers beneficial effects on cardiovascular disease and is recommended as a primary prevention strategy in type 2 diabetic patients on wide indications, including age >30 years, in the latest recommendations from the American Diabetes Association [1].

In microalbuminuric type 1 diabetic patients, elevated renal synthesis of vasodilating prostaglandins has been reported [2] and high-dose treatment with the cyclooxygenase inhibitor indomethacin (150 mg daily) reduced albumin excretion rate (AER) by 58% in these patients [2]. Similar effects have been found using high-dose ASA in combination with dipyridamole (990 mg ASA and 225 mg dipyridamole daily) or indomethacin (150 mg daily) in type 1 diabetic patients with diabetic nephropathy [3,4]. We have previously reported a lack of impact of low-dose ASA on AER in microalbuminuric type 1 diabetic patients during treatment with ACE inhibitors [5]. A masking effect of ASA on albuminuria may have a major impact on the diagnosis and monitoring during treatment of micro- or macroalbuminuria, since most type 2 diabetic patients according to recommendations will start treatment with low-dose ASA while being in the normoalbuminuric range [1].

Therefore, the primary aim of the present study was to investigate whether the effect of short-term low-dose ASA on AER could cause misclassification of micro- and macroalbuminuria and, secondly, to examine the effect on glomerular filtration rate (GFR) and endothelial dysfunction, as measured by transcapillary escape rate, in type 2 diabetic patients with elevated levels of urinary AER.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patients
Eligible patients had type 2 diabetes according to the 1985 WHO definition and an AER in the range 30–300 mg in two out of three consecutive sterile 24 h urine collections. Since ACE inhibitors may reduce AER beyond the effect of lowering of blood pressure [6,7], treatment with ACE inhibitors was stopped 8 weeks before randomization under strict control of blood pressure (n=28), but otherwise patients received usual antihypertensive treatment. This approach ensured that all included patients would have an AER in the range, where a reduction by treatment with low-dose ASA could postpone recommended treatment with ACE inhibitors in a clinical situation [8]. In case of a blood pressure above 180/100 mmHg during the study period, additional blood pressure lowering treatment with diuretics, calcium antagonists or ß-blockers was initiated. The study protocol was in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Copenhagen County. Of 43 consecutive eligible patients, four were excluded because of prior myocardial infarction, two had prior cerebral thrombosis, three used nonsteroidal anti-inflammatory drugs, one had peptic ulcer disease and two refused to participate. Thus, 31 patients, who all gave informed consent, entered and completed the study.

Crossover design
After the run-in period, patients entered a randomized, double-blind, crossover trial. The randomization was individual with concealed, computer-generated envelopes. The code was kept at the manufacturer of the tablets and not broken until all data were entered in a database. Patients were allocated to take one tablet of ASA 150 mg (Albyl; LEO A/S, Copenhagen) or one matching placebo tablet in the morning. After 4 weeks of treatment there was a 2 week washout period before patients crossed over to the opposite treatment for another 4 weeks [9]. Fifteen patients were given active treatment as the initial intervention and 16 were given placebo.

Measurements
Measurements were performed after a 12 h fast at the end of each treatment period of the double-blind crossover phase unless otherwise noted.

Transcapillary escape rate of albumin (TERalb) was determined as the rate constant of the mono-exponential decrease in plasma radioactivity over the first 60 min after injection of tracer albumin, as calculated by the least squares method described in detail elsewhere [10].

Glomerular filtration rate was measured after single intravenous injection of 3.7 MBq 51Cr-EDTA immediately after termination of the TERalb examination [11].

Urinary albumin excretion rate was measured by ELISA in three consecutive 24 h urine collections completed immediately before each visit.

Blood pressure. Supine blood pressure values were measured twice in both arms with a Hawksley random zero sphygmomanometer after at least 30 min rest and the average of these measurements was used.

Assays. Haemoglobin A1c (HbA1c) was measured from venous blood samples with high-performance liquid chromatography (Variant; Bio-Rad Laboratories, USA). Normal range of HbA1c in our laboratory is 4.1–6.4%. Serum total-cholesterol was measured by chromatography.

Statistical analysis
Results are expressed as means with SD or 95% confidence interval (CI), when appropriate. Urinary AER and fractional clearance of albumin are expressed as geometric mean (antilog 2.5% percentile to antilog 97.5% percentile for the average of the logged values) due to positive skewness of the distribution. Comparisons at baseline were performed using Student's t-test, Mann–Whitney U-test or {chi}2-test when appropriate. We used paired Student's t-test to compare differences between the variables during the two phases of the crossover part of the study. The means of the logged values of urinary AER and fractional clearance of albumin have been used for comparison of these variables and the difference is expressed as percentage reduction with active treatment. Data were tested for a period effect and a treatment-period interaction with a two-sample t-test as described [12]. A sample-size calculation was performed giving that a minimum of 30 patients were needed to detect a 20% change in urinary AER with a two-sided {alpha}=0.05 and ß=0.8 [5].



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Run-in phase
Twenty-eight of the 31 patients who entered the study (10 females, 21 males) were treated with ACE inhibitors at this time and had to stop this treatment 8 weeks before randomization. Geometric mean for AER was 123 (68–189) mg/24 h with a mean blood pressure of 145 (±18)/86 (±9) mmHg. During run-in, AER increased to 199 (117–326) mg/24 h (P=0.003) and mean blood pressure to 149 (±17)/88 (±11) mmHg (P=0.01). The mean age at randomization was 56.3 (±7.1) years with average known diabetes duration of 11.9 (±4.3) years. Mean glycated HbA1c was 8.7 (±0.3) %. Five patients were treated with insulin as monotherapy, 11 patients with insulin and oral hypoglycaemic agents (OHA) and 15 patients with OHA. Seven patients were smokers. During the run-in period, five patients had albuminuria above 300 mg per 24 h. One patient started additional blood pressure lowering treatment with a calcium antagonist during this period. No significant differences were found between patients starting with placebo treatment and patients starting with active treatment at baseline for any of these variables.

Randomized, double-blind, crossover phase
Table 1Go shows results after each of the two treatment periods. No patients had AER below 30 mg/24 h in either of the two treatment periods. We detected no significant order-of-treatment effect. No change in medication, except shift from active to placebo tablets and vice versa, was recorded in any patient during this period. The number of smokers remained unchanged throughout the crossover period.


View this table:
[in this window]
[in a new window]
 
Table 1.  Clinical and biochemical variables during active treatment with 150 mg ASA and placebo treatment in 31 type 2 diabetic patients with elevated levels of urinary AER throughout the crossover trial

 

Compliance and side effects
Adherence was high with >99% of tablets taken using simple counting of the tablets during both treatment periods.

Two patients (6%) reported dyspepsia during placebo treatment compared with one patient during active treatment (3%). One patient who was treated with ASA during the first treatment period was admitted to hospital with a bleeding gastric ulcer 51 days after termination of the second treatment period.



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Our randomized, double-blind, crossover trial has demonstrated that short-term treatment with 150 mg ASA daily does not have any significant impact on urinary AER, GFR and TERalb in type 2 diabetic patients with elevated levels of AER. Consequently, primary and secondary prevention of cardiovascular disease with low-dose ASA treatment does not confound the monitoring of micro- and macroalbuminuria in these patients.

In the kidney, the effect of blocking cyclooxygenase on glomerular function is an interaction between the production of vasodilating prostaglandins and vasoconstrictive thromboxanes [13]. Increased renal synthesis of prostaglandins occurs in both human and experimental diabetes [2]. High-dose treatment with indomethacin (150 mg/day), or ASA in combination with dipyridamole (990 mg/day and 225 mg/day, respectively) reduced renal prostaglandin synthesis and AER, while GFR remained unchanged [2,3]. These effects occurred shortly after start of treatment. Despite an increased renal production of vasodilating prostaglandins, the ratio between stable urinary metabolites of prostaglandins and thromboxane is decreased in type 2 diabetic patients with micro- or macroalbuminuria, suggesting an even further increase in intrarenal thromboxane production in these patients [14]. Our study showed no change in kidney function as measured by AER, fractional clearance of albumin and GFR during short-term treatment with low-dose ASA. We have, however, no direct information on intrarenal production or excretion of prostaglandins or thromboxanes.

The observed non-significant reduction in the primary outcome AER was 2.0% (95% CI, 15–13%) in the present study. We had 80% power to detect a 20% change in AER and as a consequence the risk for a type 2 error is large given the observed reduction, unless numerous patients were included in the study. However, a reduction in AER of the observed size would not be large enough to justify changes in the definitions of micro- and macroalbuminuria. Patients in the present study did not receive treatment with ACE inhibitors during the study period in order to imitate the clinical situation, where a patient with type 2 diabetes would start treatment with low-dose ASA as a primary prevention strategy before micro- or macroalbuminuria had been diagnosed. In case of a marked reduction in AER, this effect could interfere with the diagnosis of micro- or macroalbuminuria, thus postponing recommended treatment against increased AER. It should be noted, however, that mean AER at randomization was 199 mg/24 h and thus substantially higher than the diagnostic level for microalbuminuria. As a consequence, we cannot be certain that a difference in AER during treatment with ASA does not exist at lower levels of AER, although this was not the case in a similar study in microalbuminuric type 1 diabetic patients [5]. Whether low-dose treatment with ASA in micro- or macroalbuminuric type 2 diabetic patients already treated with ACE inhibitors has any clinical impact on the monitoring effect of albuminuria lowering treatment also remains to be elucidated. However, in our previous study in type 1 diabetic patients with microalbuminuria, this was not the case [5].



   Notes
 
Correspondence and offprint requests to: Peter Gæde, MD, Steno Diabetes Center, Niels Steensens Vej 2, DK-2820 Gentofte, Copenhagen, Denmark. Email: p.gaede{at}dadlnet.dk Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. American Diabetes Association. Aspirin therapy in diabetes. Diabetes Care2001; 23 [Suppl 1]:S62–S63
  2. Mathiesen ER, Hommel E, Olsen UB, Parving H-H. Elevated urinary prostaglandin excretion and the effect of indomethacin on renal function in incipient diabetic nephropathy. Diab Med1988; 5:145–149[ISI][Medline]
  3. Hopper AH, Tindall H, Davies JA. Administration of aspirin-dipyridamole reduces proteinuria in diabetic nephropathy. Nephrol Dial Transplant1989; 4:140–143[Abstract]
  4. Hommel E, Mathiesen ER, Arnold-Larsen S, Edsberg B, Olsen UB, Parving H-H. Effects of indomethacin on kidney function in type 1 (insulin-dependent) diabetic patients with nephropathy. Diabetologia1987; 30:78–81[ISI][Medline]
  5. Hansen HP, Gæde PH, Jensen BR, Parving H-H. Lack of impact of low-dose acetylsalicylic acid on kidney function in type 1 diabetic patients with microalbuminuria. Diabetes Care2000; 23:1742–1745[Abstract]
  6. Bohlen L, de Courten M, Weidmann P. Comparative study of the effect of ACE-inhibitors and other antihypertensive agents on proteinuria in diabetic patients. Am J Hypertens1994; 7:84s–92s[Medline]
  7. Ravid M, Savin H, Jutrin I, Bental T, Katz B, Lishner M. Long-term stabilizing effect of angiotensin-converting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type II diabetic patients. Ann Intern Med1993; 118:577–581[Abstract/Free Full Text]
  8. Mogensen CE. Microalbuminuria, blood pressure and diabetic renal disease: origin and development of ideas. Diabetologia1999; 42:263–285[CrossRef][ISI][Medline]
  9. Benedek IH, Joshi AS, Pieniaszek HJ, King SP, Kornhauser DM. Variability in the pharmacokinetics and pharmacodynamics of low dose aspirin in healthy male volunteers. J Clin Pharmacol1995; 35:1181–1186[Abstract/Free Full Text]
  10. Parving H-H, Rossing N, Nielsen SL, Lassen NA. Increased capillary escape rate of albumin, IgG and IgM after plasma volume expansion. Am J Physiol1974; 227:245–250[Free Full Text]
  11. Brøchner-Mortensen J, Rødbro P. Comparison between total and renal plasma clearance of [51Cr]EDTA. Scand J Clin Lab Invest1976; 36:247–249[ISI][Medline]
  12. Altman DG. Crossover trials. In: Altman DG, ed. Practical Statistics for Medical Research. Chapman & Hall, London, UK: 1997;467–471
  13. Zambraski EJ. The effects of nonsteroidal anti-inflammatory drugs on renal function: experimental studies in animals. Semin Nephrol1995; 15:205–213[ISI][Medline]
  14. Umeda F, Kuroki T, Nawata H. Prostaglandins and diabetic nephropathy. J Diabetes Complications1995; 9:334–336[CrossRef][ISI][Medline]
Received for publication: 6. 2.02
Revision received 12. 9.02.