Abstract
Dipyridamole has been shown to decrease proteinuria and improve renal function progression especially in early chronic kidney disease (CKD) patients with glomerulonephropathy. A combination therapy of dipyridamole with aspirin could prevent second strokes in the general population. Whether these effects of dipyridamole are also true in advanced CKD patients and whether dipyridamole could improve renal outcomes or patient survival is unknown. We retrospectively analyzed an observational cohort of 3074 participants with CKD stage 3–5 from southern Taiwan, of whom 871 (28.3%) had received dipyridamole treatment ≥50 mg/d for ≥3 months and more than half of the observation period. The mean age was 63.6 ± 13.4 years and the mean estimated glomerular filtration rate (eGFR) was 25.5 mL/min/1.73 m2. After inverse probability of treatment weighted adjustment by propensity score, there were no differences between the dipyridamole‐treated and untreated groups. Dipyridamole treatment was associated with decreased odds for rapid eGFR decline [odds ratio, 0.755; 95% confidence interval (CI), 0.595–0.958; p = 0.007] and progression of urine protein‐to‐creatinine ratio (odds ratio, 0.655; 95% CI, 0.517–0.832; p = 0.002). In survival analysis, the dipyridamole‐treated group was also associated with a decreased risk for end‐stage renal disease (hazard ratio, 0.847; 95% CI, 0.733–0.980; p = 0.011) and all‐cause mortality (hazard ratio, 0.765; 95% CI, 0.606–0.971; p = 0.001) but not for cardiovascular events. Our findings demonstrate that dipyridamole treatment is significantly associated with better renal outcomes and patient survival in patients with CKD stage 3–5. Further investigations are warranted to confirm these independent positive effects.
Keywords: Cardiovascular disease, Chronic kidney disease, Dipyridamole, End‐stage renal disease, Mortality
Introduction
The increasing global prevalence of chronic kidney disease (CKD), which leads to end‐stage renal disease (ESRD) and premature cardiovascular disease (CVD), has profound impacts on public health and economic burden [1]. The current practice guideline proposes effective strategies of early detection of high‐risk groups and provision of comprehensive management in order to prevent and slow down the progression of CKD [[1], [2]]. Current approaches focus on slowing disease progression, reducing proteinuria, and preventing related complications through interventions with renin–angiotensin–aldosterone system blockades, glycemic and blood pressure control, and dietary protein restriction [[2], [3]]. However, many patients with CKD still progress to ESRD and exhibit adverse cardiovascular outcomes and increased mortality under the current treatments, especially in the population with lower estimated glomerular filtration rate (eGFR) and higher albuminuria [[4], [5]].
Dipyridamole, either through monotherapy or in combination with other antiplatelet agents or immunosuppressants, has been widely used in diabetic nephropathy and various primary glomerulopathies for its therapeutic effects on proteinuria and variable effect on renal progression. These positive reports have been found for patients with diabetic kidney disease [6], IgA nephropathy [[7], [8]], and membranoproliferative glomerulonephritis [9]. As in the consensus reports, proteinuria has been considered a surrogate outcome of CKD. It is still undetermined whether dipyridamole plays an effective role in renal outcomes in terms of preventing ESRD in patients with more advanced CKD.
Furthermore, CVD is the main cause of morbidity and mortality in patients with CKD [10]. Previous studies have reported the efficacious effect of dipyridamole in CVD. A combination therapy of dipyridamole with aspirin has been shown to prevent second strokes in the general population [11]. A systemic review demonstrated that dipyridamole prevents the risk of recurrent vascular events but does not reduce the risk of vascular death for patients with vascular disease [12]. Moreover, Jardine et al. [13] also reported that another antiplatelet agent, aspirin, resulted in better reduction of the major cardiovascular (CV) events and mortality in hypertensive patients with CKD than in those with normal kidney function. However, the beneficial effects of antiplatelet therapy on CV outcome and mortality are still unproven for patients with CKD and must be taken with caution because of the potential hazards of bleeding based on a systematic review and meta‐analysis [14]. Thus, it is worthwhile to investigate whether dipyridamole exhibits protective benefits on CV events or overall mortality in patients with CKD.
In the current study, we aimed to investigate whether dipyridamole treatment has a positive role in improving proteinuria and the progression of eGFR, the development of ESRD, CV events, and all‐cause mortality in CKD stage 3–5 patients from an observational CKD cohort.
Methods
Participants
Between November 11, 2002 and May 31, 2009, 3749 patients were enrolled in the Integrated CKD Care Program from two affiliated hospitals of Kaohsiung Medical University in southern Taiwan as described in detail previously [[15], [16]]. They were followed up until July 31, 2010. The following were excluded: 356 patients with CKD stage 1–2; 90 patients lost to follow up in <3 months; and 229 patients who received medications for <3 months. Thus the final study population was 3074 CKD stage 3–5 patients.
Demographics and medical information
Baseline information included age, sex, primary renal diseases, blood pressure, body mass index, comorbidities, life styles, as well as medication histories. Laboratory assessments included eGFR derived from the four‐variable Modification of Diet in Renal Disease Study equation [17], serum albumin, total cholesterol, triglyceride, C‐reactive protein, total calcium, phosphate, uric acid, hemoglobin, and glycated hemoglobin. Urine protein loss was evaluated by the urine protein‐to‐creatinine ratio (UPCR) and dipstick. All data were collected and averaged from 3 months before to 3 months after enrollment. Dipyridamole treatment was defined as the daily use of dipyridamole ≥50 mg/d for >3 months and more than half of the observation period. Other medication treatment was also defined as their usage for >3 months and more than half of the observation period.
Study outcomes
The eGFR decline rate, progression of UPCR and incidence of renal replacement therapy (RRT), CV events, and all‐cause mortality were assessed. The rapid renal progression was defined as the eGFR slope <–5 mL/min/1.73 m2/y [16]. The significant progression of proteinuria was defined as increased UPCR >100 mg/g/y, which was the cut‐off value of the lowest quartile from our CKD cohort population in this study. The RRT was defined as patients reaching kidney failure that demanded the commencement of hemodialysis, peritoneal dialysis, and renal transplantation.
CV events were defined as the development of acute coronary syndrome or acute stroke, hospitalization for peripheral arterial occlusion disease or congestive heart failure, and death by the aforementioned causes. Survival status and cause of death were ascertained by a review of death certificates using charts or the National Death Index.
Statistical analyses
Continuous variables with normal distribution were presented as mean ± standard deviation and analyzed by Student t test. Continuous data with skewed distribution were expressed as median with interquartile range and were compared using the Mann–Whitney U test. Categorical data were analyzed using the Chi‐square test. Cox's hazard proportional models adjusted for baseline covariates were used to determine the association of dipyridamole with all‐cause mortality, CV events, and incidence of ESRD. Subgroup analyses, based on tests for interaction, were performed to examine the difference in treatment effects between selected groups [18]. Models for the all‐cause mortality included patients who reached RRT and were censored only at death or the end of follow up. Models for CV events were censored at the development of the aforementioned events, death, or the end of follow up. Models for ESRD were censored at the commencement of RRT, death, or the end of follow up. Binary logistic regression analysis was used to evaluate the relationship between dipyridamole and eGFR decline rate as well as progression of proteinuria.
Propensity score methods were used for reducing the selection bias on the estimate of the treatment effect in observational studies [[19], [20]]. Adjustments for the differences between dipyridamole treated and untreated groups were performed by using the inverse probability of treatment weighted (IPTW) estimator [21]. The propensity score for dipyridamole treatment of each patient was obtained by fitting a logistic regression model that included the predictor variable (i.e., dipyridamole‐treated or untreated patients) as an outcome and all baseline covariates. After the propensity score was constructed, we calculated the propensity score weight as the inverse of the propensity score. Then, the propensity score‐weighted t test was used to analyze the differences between dipyridamole‐treated and untreated groups. Furthermore, the propensity score was used as an additional covariate in the Cox's hazard proportional models for outcome analyses.
Statistical analyses were performed using SPSS, version 18.0, (SSPS Inc., Chicago, IL, USA). All statistical tests were two‐tailed, and statistical significance was assumed for p < 0.05.
Results
Clinical characteristics and medical treatment before and after IPTW adjustment
In the follow up (median, 2.7 years; range, 1.6–4.2 years), a total of 3074 participants of CKD stage 3–5 with an average age of 63.6 ± 13.4 years and 58.1% males were included for analysis. Among them, 871 (28.3%) participants had received dipyridamole treatment for >3 months and more than half of the follow‐up period. Table 1 shows the clinical characteristics and distribution between dipyridamole‐treated and untreated groups before and after IPTW adjustment. Before IPTW adjustment, there were significant differences in sex, and several clinical and laboratory parameters between the two groups. After IPTW adjustment, the mean eGFR was 25.6 mL/min/1.73 m2 and the mean UPCR was 932 mg/g without difference in both groups and the other variables were also similar between the two groups except for a higher percentage of alcohol drinkers in the dipyridamole‐untreated group.
Table 1.
Baseline demographic and clinical characteristics of participants before and after inverse probability of treatment weighted adjustment.
| Characteristics | Number of patients | Percent distribution a | ||||
|---|---|---|---|---|---|---|
| DIPY treated (n = 871) | DIPY untreated (n = 2203) | Before adjustment | After adjustment | |||
| DIPY treated | DIPY untreated | DIPY treated | DIPY untreated | |||
| Male | 553 | 1233 | 63.5 | 56.0* | 58.9 | 58.9 |
| Age (y) | 62.9 ± 13.6 | 63.9 ± 13.4 | 63.6 ± 13.6 | 63.6 ± 13.5 | ||
| DM | 220 | 767 | 25.3 | 34.8* | 28.7 | 28.6 |
| Hypertension | 391 | 1035 | 44.9 | 47 | 45.8 | 46.6 |
| CVD | 190 | 609 | 21.8 | 27.6* | 24.4 | 24.3 |
| Smoker | 200 | 510 | 23 | 23.2 | 22.1 | 23.4 |
| Alcohol use | 89 | 276 | 10.2 | 12.5 | 9.3 | 12.7* |
| MBP (mmHg) | 99.1 ± 13.6 | 99.9 ± 13.7 | 99.5 ± 14.0 | 99.7 ± 13.8 | ||
| BMI (kg/m2) | 24.8 ± 3.8 | 24.7 ± 4.0 | 24.7 ± 4.1 | 24.7 ± 4.0 | ||
| eGFR (mL/min/1.73 m2) b | 25.5 ± 15.0 | 25.6 ± 14.9 | 25.6 ± 15.3 | 25.6 ± 15.1 | ||
| CKD stage | ||||||
| Stage 3 | 333 | 823 | 38.2 | 37.4 | 37.8 | 37.5 |
| Stage 4 | 249 | 684 | 28.6 | 31 | 30.5 | 29.8 |
| Stage 5 | 289 | 696 | 33.2 | 31.6 | 31.2 | 32.2 |
| UPCR (mg/g) | 977 ± 376 | 891 ± 367 | 935 ± 371 | 928 ± 370 | ||
| Proteinuria | ||||||
| − | 265 | 588 | 30.4 | 26.7* | 27.3 | 27.3 |
| + | 257 | 628 | 29.5 | 28.5 | 28.8 | 28.8 |
| ++ | 199 | 529 | 22.8 | 24 | 23.6 | 23.6 |
| +++ ∼ ++++ | 150 | 458 | 17.3 | 20.8* | 18.9 | 18.9 |
| Albumin (g/dL) | 3.9 ± 0.5 | 3.8 ± 0.5* | 3.8 ± 0.5 | 3.8 ± 0.5 | ||
| Hb (g/dL) | 11.2 ± 2.3 | 11.0 ± 2.3* | 11.0 ± 2.4 | 11.0 ± 2.3 | ||
| UA (mg/dL) | 7.8 ± 1.9 | 7.9 ± 2.0 | 7.8 ± 2.0 | 7.9 ± 2.0 | ||
| Ca (mg/dL) | 9.1 ± 0.7 | 9.1 ± 0.8 | 9.0 ± 0.8 | 9.0 ± 0.8 | ||
| P (mg/dL) | 4.3 ± 1.1 | 4.4 ± 1.2 | 4.3 ± 1.2 | 4.3 ± 1.2 | ||
| CHOL (mg/dL) | 189 ± 55 | 191 ± 55 | 196 ± 55 | 196 ± 54 | ||
| TG (mg/dL) | 159 ± 143 | 154 ± 141* | 158 ± 143 | 155 ± 141 | ||
| HbA1c (%) | 6.2 ± 1.4 | 6.6 ± 1.7* | 6.5 ± 0.9 | 6.5 ± 2.4 | ||
| CRP (mg/L) | 0.9 ± 1.0 | 1.1 ± 0.9* | 1.1 ± 0.9 | 1.1 ± 0.8 | ||
*p < 0.05 (DIPY treated vs. DIPY untreated).
BMI = body mass index; Ca = total serum calcium; CHOL = total cholesterol; CKD = chronic kidney disease; CRP = C‐reactive protein; CVD = cardiovascular diseases; DIPY = dipyridamole; DM = diabetes mellitus; eGFR = estimated glomerular filtration rate; Hb = hemoglobin; HbA1c = glycated hemoglobin; MBP = mean blood pressure; P = serum phosphate; TG = triglycerides; UA = uric acid; UPCR = urine protein‐to‐creatinine ratio.
Continuous variables are expressed as mean ± standard deviation or median (interquartile range), and examined by Student t test or Mann–Whitney U test; categorical data expressed as percent distribution unless otherwise stated, and examined by Chi‐square test.
eGFR was derived from the four‐variable Modification of Diet in Renal Disease Study equation.
The prescribed medications are listed in Table 2. Before IPTW adjustment, the dipyridamole‐treated group had received more medications of angiotensin‐converting enzyme inhibitor (ACEI), α‐blockers, phosphate binders, and erythropoietin stimulating agent, but less oral hypoglycemic drugs, nitrates, and low dose‐aspirin. After IPTW adjustment, the rates of medical treatments between the two groups were similar.
Table 2.
Summary of medications prescribed in participants before and after inverse probability of treatment weighted adjustment.
| Characteristics | Number of patients | Percent distribution a | ||||
|---|---|---|---|---|---|---|
| DIPY treated (n = 871) | DIPY untreated (n = 2203) | Before adjustment | After adjustment | |||
| DIPY treated | DIPY untreated | DIPY treated | DIPY untreated | |||
| RAAS blockades | ||||||
| ACEI | 151 | 298 | 17.3 | 13.5* | 15.7 | 13.7 |
| ARB | 388 | 1005 | 44.5 | 45.6 | 43.3 | 46.1 |
| Other antihypertensive drugs | ||||||
| α‐blockers | 104 | 173 | 11.9 | 7.9* | 9.1 | 7.7 |
| β‐blockers | 185 | 475 | 21.2 | 21.6 | 21.7 | 21.3 |
| Calcium channel blockers | 338 | 785 | 38.8 | 35.6 | 35.8 | 36.5 |
| Vasodilators | 45 | 109 | 5.2 | 4.9 | 5.2 | 4.9 |
| Antilipid drugs | ||||||
| Statins | 223 | 560 | 25.6 | 25.4 | 25.9 | 25.3 |
| Fibrates | 21 | 78 | 2.4 | 3.5 | 2.4 | 3.5 |
| Diuretics | ||||||
| Furosemide | 163 | 391 | 18.7 | 17.7 | 17.6 | 18 |
| Thiazides | 33 | 55 | 3.8 | 2.5 | 3.3 | 2.5 |
| Antidiabetic drugs | ||||||
| Insulin | 64 | 209 | 7.3 | 9.5 | 8 | 7.6 |
| OHD | 173 | 566 | 19.9 | 25.7* | 22 | 23 |
| Others | ||||||
| Nitrates | 48 | 196 | 5.5 | 8.9* | 5.2 | 5.2 |
| Aspirin | 144 | 454 | 16.5 | 20.6* | 18.3 | 18.3 |
| Pentoxifylline | 69 | 202 | 7.9 | 9.2 | 8.4 | 9.1 |
| Phosphate binders | 311 | 450 | 35.7 | 20.4* | 14.2 | 13.7 |
| ESA | 286 | 592 | 32.8 | 26.9* | 27.6 | 27.5 |
*p < 0.05 (DIPY treated vs. DIPY untreated).
ACEI = angiotensin‐converting enzyme inhibitor; ARB = angiotensin II receptor blocker; DIPY = dipyridamole; ESA = erythropoietin stimulating agent; OHD = oral hypoglycemic drugs; RAAS = renin–angiotensin–aldosterone system.
Categorical data expressed as percent distribution unless otherwise stated, and examined by Chi‐square test.
Association between dipyridamole and surrogate renal outcomes
As shown in Table 3, the dipyridamole‐treated group was associated with less rapid renal progression [odds ratio (OR), 0.755; 95% confidence interval (CI), 0.595–0.958; p = 0.007]. Other medications and factors associated with less rapid renal progression included the concomitant uses of ACEI/angiotensin II receptor blockers (ARB), greater age, higher body mass index (BMI), hemoglobin, and plasma albumin (all p < 0.05). In contrast, proteinuria was associated with rapid renal progression. Furthermore, the dipyridamole‐treated group was significantly associated with decreased progression of proteinuria (OR, 0.655; 95% CI, 0.517–0.832; p = 0.002) based on the definition with UPCR change >100 mg/g/y. Other medications and factors associated with decreased progression of proteinuria included the concomitant uses of ACEI/ARB and nitrates, female sex, higher levels of BMI, baseline eGFR, and plasma albumin (all p < 0.05). In contrast, significant proteinuria progression was associated with the concomitant uses of diuretics and phosphate binders, and higher levels of serum phosphate (all p < 0.05).
Table 3.
Binary logistic regression analysis of estimated glomerular filtration rate (eGFR) decline and progression of urinary protein‐to‐creatinine (UPCR) ratio.
| Medications | eGFR decline a | UPCR progression b |
|---|---|---|
| OR (95% CI) | OR (95% CI) | |
| Dipyridamole | 0.755 (0.595–0.958)* | 0.655 (0.517–0.832)* |
| ACEI/ARB | 0.746 (0.585–0.953)* | 0.763 (0.605–0.963)* |
| Other antihypertensive drugs | 0.908 (0.639–1.291) | 1.347 (0.996–1.822) |
| Antidiabetic drugs | 1.122 (0.823–1.533) | 0.863 (0.626–1.194) |
| Antilipid drugs | 1.034 (0.798–1.343) | 1.134 (0.864–1.489) |
| Diuretics | 1.255 (0.864–1.827) | 2.099 (1.503–2.934) |
| Aspirin | 1.023 (0.728–1.440) | 0.733 (0.523–1.030) |
| Phosphate binders | 0.690 (0.292–1.635) | 2.468 (1.218–4.996) |
| Nitrates | 0.731 (0.428–1.248) | 0.513 (0.315–0.834) |
| Pentoxifylline | 0.912 (0.660–1.304) | 0.952 (0.712–1.341) |
*p < 0.05 indicates significant association with eGFR decline or progression of UPCR.
ACEI = angiotensin‐converting enzyme inhibitor; ARB = angiotensin II receptor blocker; CI = confidence interval; OR = odds ratio.
eGFR slope <−5 mL/min/1.73 m2/y is defined as rapid renal progression.
Annual UPCR change >100 mg/g/y is defined as significant progression of proteinuria.
Association between dipyridamole and ESRD
There were 295 patients (10.1 events/100 person–years) and 646 patients (11.0 events/100 person–years) who reached ESRD in the dipyridamole‐treated and untreated groups, respectively. The dipyridamole‐treated group was associated with less risk for ESRD [hazard ratio (HR), 0.847; 95% CI, 0.733–0.980; p = 0.011] compared to the untreated group after adjusting the propensity score and covariates. In addition, the concomitant uses of ACEI/ARB, greater age, female sex, higher levels of baseline eGFR, hemoglobin, and plasma albumin were associated with less risk for ESRD (all p < 0.05; Table 4). Conversely, the patients with concomitant uses of antihypertensive drugs, antidiabetic medication, diuretics, and erythropoietin stimulating agents, higher blood levels of total cholesterol, phosphate, as well as severe proteinuria were associated with a higher risk for ESRD (all p < 0.05). The results of prespecified subgroup analyses are shown in Fig. 1A. The dipyridamole‐treated group was associated with less risk for ESRD in the nondiabetes mellitus subgroup (HR, 0.76; 95% CI, 0.64–0.91) than the diabetes mellitus subgroup (HR, 1.12; 95% CI, 0.86–1.45) with borderline significance for interaction (p = 0.063).
Table 4.
Cox's proportional hazard models of end‐stage renal disease, all‐cause mortality, and cardiovascular events.
| Medications | End‐stage renal disease | All‐cause mortality | Cardiovascular events |
|---|---|---|---|
| HR (95% CI) | HR (95% CI) | HR (95% CI) | |
| Dipyridamole | 0.847 (0.733–0.980)* | 0.765 (0.606–0.971)* | 1.018 (0.830–1.257) |
| ACEI/ARB | 0.760 (0.651–0.889)* | 0.619 (0.488–0.785)* | 0.664 (0.534–0.826)* |
| Other antihypertensive drugs | 1.286 (1.025–1.613)* | 0.746 (0.543–1.029) | 1.132 (0.835–1.536) |
| Antidiabetic drugs | 1.353 (1.080–1.699)* | 0.596 (0.443–0.803)* | 1.201 (0.906–1.594) |
| Antilipid drugs | 1.190 (1.000–1.419)* | 0.812 (0.611–1.083) | 1.057 (0.839–1.332) |
| Diuretics | 1.393 (1.093–1.776)* | 1.515 (1.077–2.133 | 1.817 (1.324–2.497)* |
| Aspirin | 1.133 (0.912–1.412) | 0.862 (0.620–1.198) | 1.492 (1.134–1.966)* |
| Phosphate binders | 1.249 (0.730–2.136) | 0.770 (0.357–1.658) | 1.480 (0.714–3.068) |
| Nitrates | 0.864 (0.623–1.200) | 0.733 (0.446–1.204) | 1.208 (0.801–1.825) |
| Pentoxifylline | 0.910 (0.643–1.287) | 0.978 (0.858–1.115) | 1.024 (0.787–1.226) |
*p < 0.05 indicates significant association with end‐stage renal disease, all‐cause mortality, and cardiovascular events.
ACEI = angiotensin‐converting enzyme inhibitor; ARB = angiotensin II receptor blocker; CI = confidence interval; HR = hazard ratio.
Figure 1.
Effects of dipyridamole therapy in selected subgroups. The forest plots show the hazard ratio (HR) and 95% confidence interval (CI) for: (A) end‐stage renal disease (ESRD); and (B) all‐cause mortality in selected subgroups of patients. CKD = chronic kidney disease; CVD = cardiovascular disease; DM = diabetes mellitus; RAAS = renin–angiotensin–aldosterone system.
Association between dipyridamole and all‐cause mortality
There were 101 patients (3.5 events/100 person–years) and 340 patients (5.8 events/100 person–years) who died in the dipyridamole‐treated and untreated groups, respectively. After adjusting covariates using the propensity score method, dipyridamole treatment was associated with reducing all‐cause mortality by 23.5% (HR, 0.765; 95% CI, 0.606–0.971; p = 0.001). Moreover, concomitant uses of ACEI/ARB and antidiabetic drugs, female sex, higher levels of baseline eGFR, plasma albumin level, and BMI were also associated with less all‐cause mortality (all p < 0.05). By contrast, use of diuretics, greater age, comorbidities of CVD and diabetes, higher blood C‐reactive protein level, and proteinuria were significantly associated with increased risk of all‐cause mortality (all p < 0.05). The result of prespecified subgroup analyses showed insignificant interactions in all subgroups (Fig. 1B).
Association between dipyridamole and cardiovascular events
There were 137 patients (4.7 events/100 person–years) and 350 patients (5.9 events/100 person–years) who had CV events in the dipyridamole‐treated and untreated groups, respectively. As shown in Table 4, the dipyridamole‐treated group was not associated with lower risk for CV events. The concomitant uses of ACEI/ARB, female sex, higher BMI, and higher levels of plasma albumin were associated with lower risk for CV events (all p < 0.05), whereas concomitant uses of diuretics and aspirin, greater age, and previous CVD were associated with higher risks for CV events (all p < 0.05).
Discussion
In our study, dipyridamole treatment was associated with decreased risk for rapid renal progression, significant proteinuria progression, development of ESRD, and all‐cause mortality in CKD stage 3–5 patients. These beneficial effects of dipyridamole were validated by using propensity score methods for bias reduction [[19], [22]]. This is the first study to provide long‐term positive effects of dipyridamole on renal outcomes and patient survival in CKD patients.
There are several underlying mechanisms by which dipyridamole may exert its renoprotective effects. First, dipyridamole may inhibit platelet activation and aggregation by increasing adenosine level and inhibiting cAMP‐phosphodiesterase [23]. Moreover, it may stimulate vasodilation via enhancing the nitric oxide pathway [24] and also act as an antioxidant [25]. Additionally, dipyridamole may exert renoprotective effects through inhibiting cellular proliferation of human mesangial cells and renal fibroblasts and extracellular matrix accumulation [26]. In vivo, dipyridamole alone or along with ACEI has been proved to attenuate renal progression and microalbuminuria via increasing effective renal plasma flow in renal mass reduction rats [27] and enhanced nitric oxide expression in streptozotocin‐induced diabetic rats [28].
In previous human studies, dipyridamole was found to play an effective role in improving proteinuria in various kidney diseases, which is consistent with our finding. In patients with IgA nephropathy, combination therapy of dipyridamole, cyclophosphamide, and warfarin significantly improved proteinuria [[8], [29]]. A meta‐analysis of antiplatelet treatment for IgA nephropathy demonstrated the efficacious effect of dipyridamole in reducing the risk for proteinuria by 41% [7]. In addition, dipyridamole alone or combination therapy with aspirin or ACEI significantly reduced proteinuria in diabetic nephropathy [6] and in membranoproliferative glomerulonephritis [30].
However, the effect of dipyridamole on renal function preservation of kidney diseases is controversial. Antiplatelet therapy with dipyridamole treatment yielded a relative risk reduction of renal progression in a meta‐analysis for IgA nephropathy [7]. By contrast, a study for IgA nephropathy by Woo et al. [[29], [31]] initially demonstrated stabilization of renal function by combination therapy of dipyridamole with cyclophosphamide and warfarin, but found no difference in renal function between the treated and control groups in a 5‐year post‐trial assessment. Most of the other studies also showed that combined therapy of dipyridamole with other antiplatelet agents and immunosuppressants may improve proteinuria but did not alter the renal function progression in patients with IgA nephropathy [8], type 1 diabetes [32], and membranoproliferative glomerulonephritis [[9], [30]]. However, these studies were of small scale and did not observe the hard renal outcome—ESRD. Our study, which is one of the largest studies of dipyridamole and includes ESRD as an outcome, fills the gap in this field.
Another important finding from this study is that we demonstrate a positive effect of dipyridamole on reducing all‐cause mortality in this advanced CKD cohort. Increased all‐cause and CV mortalities are the prominent worse outcomes for patients with CKD [33]. It has been proposed that bidirectional interactions between CKD and CVD lead to the development of cardiorenal syndrome and accelerate the disease process [34]. Both CKD and CVD share common risk factors and aggravating factors, such as diabetes, hypertension, dyslipidemia, and albuminuria. Treatment with renin–angiotensin–aldosterone system blockade and antiplatelet therapy would be the rational approach to modify the disease progression and improve the outcomes of both CVD and CKD. It is well established that antiplatelet agents with aspirin or clopidogrel are effective in preventing stroke, myocardial infarction, and CV death [35]. Our study has demonstrated a positive link of dipyridamole treatment with reducing the risk of all‐cause mortality. However, neither dipyridamole nor aspirin exhibit the benefit in reducing CV events in the current study. Previous reports also showed the negative effect of clopidogrel in reducing the CVD and death in patients with CKD [36]. There might be a differential CV outcome in patients with CKD compared to the general population despite preventive efforts. Additionally, CKD patients in Taiwan may have a higher possibility of developing competitive risk for ESRD than cardiovascular death as compared to western countries [37].
The current study provides several key findings of clinically crucial significance. First, we prove the beneficial effects of dipyridamole treatment on preventing ESRD in patients with CKD stage 3–5. It has been well recognized that proteinuria is a surrogate end point for progression of kidney diseases [38]. It is reasonable to speculate that improving proteinuria progression might be one of the mechanisms by which dipyridamole treatment reduces the incidence of ESRD. Although these beneficial effects might also be explained by the concurrent uses of ACEI/ARB or the influence of other potential renoprotective drugs, dipyridamole deserves more in‐depth randomized clinical trials to prove its independent renoprotective effect.
Second, the positive effect of dipyridamole in reducing all‐cause mortality is promising for patients with CKD when targeting the improvement of patient survival, although this beneficial effect could not be explained by altering the CV events. A systemic review from 29 studies reported that dipyridamole may be beneficial in decreasing recurrent vascular events for patients with vascular diseases, but it did not reduce the risk of vascular death [12]. More studies are needed to explore the associated mechanisms of this beneficial effect.
Third, some advanced CKD patients could not receive ACEI/ARB because of hyperkalemia and renovascular disease. Dipyridamole could be a candidate drug in these patients. Finally, another major advantage of choosing dipyridamole as an antiplatelet agent for CKD patients is for its better tolerance compared to aspirin and lower cost compared to clopidogrel.
However, there are several limitations in the current study. First, this is an observational study, and hence the causation of the observed relationships cannot be confirmed. Second, baseline differences still existed between the dipyridamole‐treated and untreated groups, because propensity score technology could not consider all the subtle differences between the groups. There could still be selection bias. Third, this study lacks specific data regarding other antiplatelet or antithrombotic agents, such as cilostazol that may affect the renal progression [[39], [40]]. Fourth, other medications such as uric acid lowering agents and sodium bicarbonate could be beneficial for renal disease [41]. However, there are still controversies about these medications and the percentage of their use was low in our cohort. We therefore did not include them in our analysis. Finally, our CKD patients received multiple renoprotective agents other than dipyridamole, especially the concurrent use of ACEI/ARB and other antihypertensive drugs such as pentoxifylline [41]. Their effects alone or in combination may not be eliminated by adjustment in the model. These weaknesses might confound the interpretation of results.
In conclusion, our study demonstrates that dipyridamole treatment is significantly associated with better renal outcomes and patient survival in patients with CKD stages 3–5. These beneficial results may suggest that dipyridamole treatment could be used as one of the interventional approaches for CKD patients. It warrants further investigations and randomized clinical trials to clarify the mechanisms and confirm its independent positive effects.
Conflicts of interest: All authors declare no conflicts of interest.
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