Diyabetik nefropati gelişimine aldosteron blokajının etkileri The effects of aldosterone receptor blockade on diabetic nephropathy
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2007
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info:eu-repo/semantics/openAccess
Özet
Diyabet prevalansı tüm dünyada artmaktadır. Dünya Sağlık Örgütü verilerine göre 2030 yılında diyabetli hasta sayısı 370 milyona yükselecektir. Diyabetik nefropati, endüstrileşmiş ülkelerde olduğu gibi ülkemizde de son dönem böbrek yetmezliğinin en sık nedeni olmuştur. Bundan dolayı diyabetik nefropatinin erken tanısı ve böbrek koruyucu tedavinin düzenlenmesi önemlidir. Giderek artan sayıda deneysel ve klinik veri, anjiotensin II'nin hedef organ hasarına yol açtığını ortaya koymuştur ancak renin anjiotensin aldosteron sisteminin son ürünü olan aldosteronun inflamasyon ve fibrozise yol açıcı etkilerle kardiyovasküler ve renal hasara katkıda bulunduğu uzun süre sonra anlaşılmıştır. Çalışmalar sonucu aldosteronun kardiyo- vaskülo-renal hasar patogenezinde anjiotensin II'den bağımsız etkileri olduğunu gösteren sonuçlar elde edilmiştir. Aldosteron salgısı büyük oranda anjiotensin II tarafından kontrol edilse de, anjiotensin konverting enzim inhibitörleri veya anjiotensin II-tip 1 reseptor blokerleri ile tedavi edilen hastaların önemli bir bölümünde, artmış albuminüri ve hızlanmış glomeruler filtrasyon hızı azalması ile ilişkili aldosteron kaçağı gelişebileceği bildirilmiştir. Bu nedenle çalışmamızda, üç ay süreyle 25 mg/gün dozunda uyguladığımız, aldosteron reseptör blokeri olan, spironolaktonun nefron fonksiyonlarına etkisini en az 6 aydan bu yana anjiotensin konverting enzim inhibitörü veya anjiotensin II-tip 1 reseptör blokeri kullanan mikroalbuminürik tip 2 diyabetli 20 (9 K, 11 E) hastadan oluşan kombinasyon grubunda ve bu grup ilaçları kullanmayan 11 (6 K, 5 E) mikroalbuminürik tip 2 diyabetliden oluşan spironolakton grubunda araştırdık. Kombinasyon grubunda spironolakton tedavisi mevcut anjiotensin konverting enzim inhibitörü veya anjiotensin II-tip 1 reseptör blokeri tedavisine ek olarak uygulandı. Hastaların spironolakton tedavisi öncesinde kullanmakta oldukları tedaviler çalışma boyunca değiştirilmedi. Üç aylık tedavi sonunda, kombinasyon grubunda idrarla protein atılımı (UPE, p:0.015), idrarla albumin atılımı (UAE, p:0.010) ve idrarla albumin atılımının idrar kreatininine oranı (UAE/iKr, p:0.007) anlamlı azaldı, serum potasyum düzeyi (sK+, p:0.004) anlamlı arttı. Spironolakton grubunda, UAE/iKr oranı (p:0.016) anlamlı azaldı. Tüm hastalarımız birlikte değerlendirildiğinde, UPE (p:0.019), UAE (p:0.002) ve UAE/iKr oranı (p:0.011) anlamlı azaldı, serum kreatinini (sKr, p:0.025) ve sK+ (p:0.002) anlamlı yükseldi. Kombinasyon grubunda, 12 aydan daha uzun süre anjiotensin konverting enzim inhibitörü veya anjiotensin II-tip 1 reseptör blokeri kullananlarda UPE (p:0.015), UAE (p:0.010), ve UAE/iKr oranı (p:0.007) anlamlı azalırken, 12 aydan daha kısa süre bu tedavileri kullanmış olanlarda bu parametrelerde anlamlı değişiklik oluşmadı. Tüm hastalarımızdan oluşan grupta, UAE'deki değişimle glomeruler filtrasyon hızı (GFR, r:0.525, p:0.002) değişimi pozitif, sKr değişimi (-r:0.473, p:0.007) negatif; UAE/iKr oranındaki değişimle sKr değişimi (-r:0.501, p:0.004) negatif doğrusal ilişkili bulundu. Özetle, bu çalışmada, daha önce anjiotensin konverting enzim inhibitörü veya anjiotensin II-tip 1 reseptör blokeri kullanan hastalarda daha belirgin olmak üzere, tüm diyabetik nefropatili hastalarımızda, aldosteron reseptör blokeri olan spironolakton albuminüriyi azalttı. Bulgularımız, başta anjiotensin konverting enzim inhibitörü veya anjiotensin II-tip 1 reseptör blokeri tedavisi kullanmalarına rağmen aldosteron kaçağı gelişmiş olanlar olmak üzere diyabetik nefropatili hastalarda aldosteron etkilerini baskılamaya yönelik tedavilerin yeni tedavi stratejisi olabileceğini göstermektedir. Uzun süreli böbrek koruyucu etkileri ve tolerabiliteyi tam olarak anlayabilmek için uzun süreli ve çok sayıda hastayı kapsayan çalışmaların yapılması gereklidir. Anahtar Kelimeler: Diyabetes Mellitus, Diyabetik Nefropati, Anjiotensin II, Aldosteron, Spironolakton
THE EFFECTS OF ALDOSTERONE RECEPTOR BLOCKADE ON DIABETIC NEPHROPATHY SUMMARY The prevalence of type 2 diabetes mellitus is increasing worldwide. According to recent global estimates of the World Health Organization, there will be 370 million people with diabetes by the year 2030. Increasing prevalence of diabetes mellitus and prolongation of the life-span of diabetic patients will result in a higher prevalence of diabetic nephropathy. Diabetic nephropathy has become the leading cause of end-stage renal disease in Turkey as well as in industrialized countries. Therefore, early identification and subsequent renoprotective treatment are of utmost importance. Although many experimental and clinical studies have investigated the role of angiotensin II in mediating target organ damage, relatively little attention has been paid to the role of aldosterone, the end product of the renin- angiotensin-aldosterone system. However, there are data to suggest that aldosterone may play an important role in the pathogenesis of cardiovascular-renal disease that is independent of Ang II. On the other hand, although secretion of aldosterone is in part controlled by Ang II, aldosterone escape has been observed in a substantial proportion of patients treated with angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers. Importantly, this aldosterone escape was associated with an enhanced excretion of urinary albumin and an enchanced decline in glomerular filtration rate. In this study, we aimed to evaluate the effects of 25 mg spironolactone, an aldosterone receptor antagonist, on nephron function in 20 (9 F, 11 M) type 2 diabetic patients with persistent microalbuminuria despite at least six months usage of an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker (combination group), and in eleven (6 F, 5 M) type 2 diabetic patients with microalbuminuria who never used an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker (spironolactone group). In combination group, spironolactone was added to angiotensin converting enzyme inhibitor or an angiotensin receptor blocker. The type and dose of prior treatment remained unchanged throughout the study. After a treatment period of three months, urinary protein excretion (UPE, p:0.015), urinary albumin excretion (UAE, p:0.010) and urinary albumin excretion/urinary creatinine ratio (UAE/uCr, p:0.007) were decreased, serum potassium (sK+, p:0.004) was elevated significantly in combination group. UAE/uCr ratio (p:0.016) was decreased significantly in spironolactone group. In all groups, UPE (p:0.019), UAE (p:0.002), and UAE/uCr ratio (p:0.011) were decreased, serum creatinine (sCr, p:0.025) and sK+ (p:0.002) were elevated significantly. After therapy, UPE (p:0.015), UAE (p:0.010), and UAE/uCr ratio (p:0.007) were decreased significantly in patients who used angiotensin converting enzyme inhibitor or an angiotensin receptor blocker longer than 12 months, whereas they did not change significantly in patients who used these drugs â ¤ 12 months. Changes in albuminuria correlated positively with changes in GFR (r:0.525, p:0.002), negatively with changes in sCr (-r:0.473, p:0.007), and changes in UAE/uCr ratio was correlated negatively with changes in sCr (- r:0.501, p:0.004) in all patient groups. In summary, spironolactone reduced albuminuria in type 2 diabetic patients with nephropathy. This effect occurs in addition to that obtained with the administration of the angiotensin converting enzyme inhibitor or an angiotensin receptor blocker. Our findings suggest that attenuation of aldosterone effects may become a new goal for patients with early diabetic nephropathy, and especially for those who show aldosterone escape during angiotensin converting enzyme inhibitor or an angiotensin receptor blocker treatment. Further studies are needed to evaluate the long-term renoprotective effect and tolerability of aldosterone antagonism. Key Words: Diabetes Mellitus, Diabetic Nephropathy, Angiotensin II, Aldosterone, Spironolactone
THE EFFECTS OF ALDOSTERONE RECEPTOR BLOCKADE ON DIABETIC NEPHROPATHY SUMMARY The prevalence of type 2 diabetes mellitus is increasing worldwide. According to recent global estimates of the World Health Organization, there will be 370 million people with diabetes by the year 2030. Increasing prevalence of diabetes mellitus and prolongation of the life-span of diabetic patients will result in a higher prevalence of diabetic nephropathy. Diabetic nephropathy has become the leading cause of end-stage renal disease in Turkey as well as in industrialized countries. Therefore, early identification and subsequent renoprotective treatment are of utmost importance. Although many experimental and clinical studies have investigated the role of angiotensin II in mediating target organ damage, relatively little attention has been paid to the role of aldosterone, the end product of the renin- angiotensin-aldosterone system. However, there are data to suggest that aldosterone may play an important role in the pathogenesis of cardiovascular-renal disease that is independent of Ang II. On the other hand, although secretion of aldosterone is in part controlled by Ang II, aldosterone escape has been observed in a substantial proportion of patients treated with angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers. Importantly, this aldosterone escape was associated with an enhanced excretion of urinary albumin and an enchanced decline in glomerular filtration rate. In this study, we aimed to evaluate the effects of 25 mg spironolactone, an aldosterone receptor antagonist, on nephron function in 20 (9 F, 11 M) type 2 diabetic patients with persistent microalbuminuria despite at least six months usage of an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker (combination group), and in eleven (6 F, 5 M) type 2 diabetic patients with microalbuminuria who never used an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker (spironolactone group). In combination group, spironolactone was added to angiotensin converting enzyme inhibitor or an angiotensin receptor blocker. The type and dose of prior treatment remained unchanged throughout the study. After a treatment period of three months, urinary protein excretion (UPE, p:0.015), urinary albumin excretion (UAE, p:0.010) and urinary albumin excretion/urinary creatinine ratio (UAE/uCr, p:0.007) were decreased, serum potassium (sK+, p:0.004) was elevated significantly in combination group. UAE/uCr ratio (p:0.016) was decreased significantly in spironolactone group. In all groups, UPE (p:0.019), UAE (p:0.002), and UAE/uCr ratio (p:0.011) were decreased, serum creatinine (sCr, p:0.025) and sK+ (p:0.002) were elevated significantly. After therapy, UPE (p:0.015), UAE (p:0.010), and UAE/uCr ratio (p:0.007) were decreased significantly in patients who used angiotensin converting enzyme inhibitor or an angiotensin receptor blocker longer than 12 months, whereas they did not change significantly in patients who used these drugs â ¤ 12 months. Changes in albuminuria correlated positively with changes in GFR (r:0.525, p:0.002), negatively with changes in sCr (-r:0.473, p:0.007), and changes in UAE/uCr ratio was correlated negatively with changes in sCr (- r:0.501, p:0.004) in all patient groups. In summary, spironolactone reduced albuminuria in type 2 diabetic patients with nephropathy. This effect occurs in addition to that obtained with the administration of the angiotensin converting enzyme inhibitor or an angiotensin receptor blocker. Our findings suggest that attenuation of aldosterone effects may become a new goal for patients with early diabetic nephropathy, and especially for those who show aldosterone escape during angiotensin converting enzyme inhibitor or an angiotensin receptor blocker treatment. Further studies are needed to evaluate the long-term renoprotective effect and tolerability of aldosterone antagonism. Key Words: Diabetes Mellitus, Diabetic Nephropathy, Angiotensin II, Aldosterone, Spironolactone
Açıklama
Anahtar Kelimeler
Endokrinoloji ve Metabolizma Hastalıkları, Endocrinology and Metabolic Diseases
