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  • Trombositten zengin plazma

    TROMBOSİTTEN ZENGİN PLAZMA(TZP)

    Trombositten Zengin Plazma (Platelet rich plasma:PRP)1970'lerin başında çok bileşimli kan ürünlerinin bir yan ürünü olarak geliştirilmiştir. O yıllardan beri özellikle ortopedik,1 periodontik,2 maksillofasiyal,3 plastik,4 torakal,5 damar cerrahisi6-7 ve oftalmolojide8 kullanıldığı bilinmekle birlikte, son zamanlarda dermatoloji pratiğinde de yeni endikasyonlarda kullanımı dikkat çekmektedir .

    Otolog trombositten zengin plazma; santrifüj kullanılarak kişinin kendi kanından elde edilen, büyüme faktörlerinden zengin trombosit konsantrasyonu yüksek olan plazmayı ifade eder. TZP'deki trombosit yoğunluğu ve aktivitesi tam kandakinden 4 kat daha fazladır9.Trombositler; hemostazdaki rolü yanında, doku hasarında α-granüllerinden büyüme faktörleri salgılayarak doku onarımında da önemli role sahiptir10. Alfa granülleri; trombosit kaynaklı büyüme faktörü (platelet-derived growth factor: PDGF), dönüştürücü büyüme faktörü α ve β (transforming growth factor : TGF- α ve TGF- β), epidermal büyüme faktör (epidermal growth factor: EGF) ve damarsal endotelyal büyüme faktörü (vascular endothelial growth factor: VEGF) gibi çeşitli büyüme faktörleri ayrıca sitokinler ve kemokinler içermektedir 11-14.Büyüme faktörleri, sitokin, kemokin ve integrin olarak bilinen diğer sekretuar moleküller genç trombositlerde fazladır, trombositlerin 7-10 günlük yaşam süreleri boyunca az miktarda salgılanmaya devam eder. PDGF; endotel hücrelerinin büyümesini uyararak hasarlı bölgedeki fibroblastların sayısını arttırır, nötrofil ve monositlerin farklılaşmasını sağlar. Böylece kapiller damar oluşumu, kolajen üretiminin arttırılması ve granülasyon oluşumu desteklenir. TGF- β derinin yeniden yapılandırılmasında hayati önem taşımaktadır: Örneğin yara iyileşme sürecinde bizzat kolajen sentezini uyarmasının yanında, PDGF ile birlikte inflamatuvar yanıta da katılır ve ekstrasellüler matriks sentezini uyarır12. EGF kemotaksiste rol alır, keratinosit ve fibroblastların çoğalmasını uyarır. Çoğalan fibroblastlar kolajen üretimini arttırır. VEGF endotel hücrelerin çoğalmasını uyarır, böylece yeni damar oluşumunu arttırır, mevcut kapiller damar geçirgenliğini arttırır ve hücre büyümesi ve anjiogenez için gerekli mikroçevreye katkıda bulunur. İnsülin benzeri büyüme faktörü (Insulin like growth factor: IGF), IGF-1 ve IGF-2 dahil, vasküler endotel hücreleri için kemotaktik role sahiptir. Böylece vasküler endotel hücrelerinin hasarlı alana migrasyonunu uyarır, anjiogenezi destekler ve PDGF ile birlikte endotel ve epidermis yenilenme oranını arttırır 12-16.

    TZP'nin dermatolojik kullanım alanları

    Trombositten zengin plazmanın tedavide kullanılması fikri çok miktarda büyüme faktörü içermesinden kaynaklanmıştır. Büyüme faktörleri klinik olarak kronik yaraların tedavisinde, yumuşak doku hasarında, kemik bozukluklarında, kırışıklık giderilmesinde ve akut travmalarda kullanılmaktadır.Dermatokozmetolojik uygulamalarda çeşitli endikasyonlarda yer bulmaktadır13-20. Tablo 1.'de sunulan bu kullanım alanlarında sonuçlar klinik gözlemlere dayanmakta olup, kontrollü çalışmalara gereksinim vardır.

    Eppley ve ark.13 tarafından yapılan bir araştırmada kronik, iyileşmeyen kutanöz ülserlerin tedavisinde granülasyon dokusunun epitelizasyonunu hızlandırmak için otolog trombosit faktörlerinin kullanılabileceği ileri sürülmüştür. Bu çalışmanın, kronik deri ülserlerinin iyileşmesini hızlandıran, otolog kandan elde edilen aktive edici faktörlerin kullanıldığı ilk klinik uygulama olduğu bildirilmiştir. Başka bir çalışmada, TZP derideki ülserlerde kullanılmış, dokuda granülasyon dokusu oluşumu ve epitelizasyonun hızlanmasında etkili olduğu gösterilmiştir12.

    Trombositten zengin plazma, derinin destek dokuların zaman içinde azalmasıyla ortaya çıkan yüz ve boyun kırışıklıklarında, deri sarkması ve pigmentasyon sorunlarında oldukça etkili bulunmaktadır. Deri yaşlanması; kronolojik yaşlanma sonucu derinin koruyucu fonksiyonlarında düşüş olması yanında sigara, güneşe maruziyet(fotoyaşlanma) ve çeşitli kimyasallara maruziyet gibi çevresel faktörlerin etkileşiminin doğal bir sonucudur. Fotoyaşlanmanın en önemli sebebi olan UVB'nin, dermal fibroblastlardan kolajenaz üretimini arttırdığı ve kolajenaz gen ekspresyonunu uyardığı gösterilmiştir21,22. Sürekli UVB'ye maruz kalan deride, kolajen dejenerasyonu, dermal ekstrasellüler matriks bütünlüğünün bozulması ve elastik dokudaki değişiklikler deri direncinde azalmaya neden olarak kırışıklıklara yol açar. Topikal büyüme faktörlerinin uygulanması; yeni kolajen sentezinin arttırılmasını sağlayarak foto yaşlanmış yüz derisinin gençleştirilmesi ve klinik görünümün iyileştirilmesini sağlar17. Na JI ve ark.14 kırışıklık azaltılması ve skar tedavisinde kullanılan fraksiyonel karbondioksit lazer uygulamalarından sonra hastalara TZP uygulanmasıyla, yara iyileşmesinde hızlanma, eritem gibi geçici istenmeyen etkilerde azalma ve deri sıkılığında artma olduğunu bildirmişlerdir. TZP aşırı damar oluşumuna neden olmaksızın yeterli düzeyde vaskülarizasyon sağlar. Böylece fraksiyonel yüzey yenileyici CO2 lazerden sonra gelişebilen eritem süresi kısalır14.

    TZP uygulaması üst yüz bölgesinde alın, göz kenarı kırışıklıklarında, zigomatik bölge sarkmalarında başarı ile uygulanmaktadır. Orta ve alt yüz bölgesinde burun kenarı kırışıklıklarında, çene köşeleri sarkmalarında, çene altı sarkmalarında, boyun ve dekolte kırışıklık ve sarkmalarında TZP uygulaması sonucunda etkin sonuçlar alınmaktadır23.

    Lee ve ark.15akne skarı tedavisinde ablatif karbondioksit fraksiyonel lazer uygulamasına TZP enjeksiyonunun eklenmesi sonucunda, istatistiksel olarak anlamlı olmasa da iyileşmenin daha hızlanmış olduğunu gözlemlemişlerdir. Bu çalışmada fraksiyonel lazer uyguladıktan sonra yüzün bir yanına 20 noktaya, 1.5-2 cm arayla, 0.3ml TZP intradermal olarak uygulanmış, 4 ay sonraki sonuçlar serum fizyolojik uygulanan diğer yüz yarısıyla karşılaştırılmıştır. 1 ay sonra işlem tekrarlanmıştır15.

    Jeong ve ark.24 ise tedaviye dirençli lipodermatosklerozlu bir vakada yapılan intralezyonel TZP uygulaması ile yüz güldürücü sonuç aldıklarını bildirmişlerdir.

    TZP'deki TGF-β; laminin, kolajen IV ve tenascin gibi bazal membran protein sekresyonunu uyarmaktadır. Bazal membranın hızlı onarılması sayesinde inkontinensia pigmenti gibi lezyonlar için uygulanan fraksiyonel CO2 lazerden sonra pigmentasyon gelişmediği bildirilmektedir. Öte yandan TGF- β'nın da melanogenezi azalttığı bilinmektedir25. Böylece hamilelik, yaşlılık, güneş hasarı nedeni ile oluşmuş pigmentasyon bozuklukları ve derideki skarlar ile strialarda da uygulanabilmektedir.

    TZP uygulaması ile saçlı deride, saç dökülmesi, saçlarda kırıklık, cansızlık mat görünüş şikayeti olan kişilerde başarılı sonuçlar alınmaktadır. Saç dökülmesini durdurması yanında, saç köklerini uyararak saç büyümesini aktive eder. İnce olan saçların büyümeleri aktive edildiğinde daha kalın, sağlıklı görünüme kavuşurlar. TZP uygulaması zaman içerisinde tamamen dökülmüş olan saçların yeniden çıkmasını sağlamaz, mevcut saçların daha sağlıklı olması, dökülmenin durması, saçların daha sağlıklı hale gelmesi sağlanır. Takikawa M ve ark.26 da TZP uygulamaları ile saç büyümesinde olumlu sonuçlar bildirmişlerdir.

    TZP hazırlanması ve uygulama

    Çeşitli TZP hazırlama yöntemi olsa da bunların çok azı FDA tarafından onaylanmıştır(Örn:Smart PReP ve trombosit konsantrasyon toplama sistemi:PCCS). Farklı sistemlerle elde edilen plazmadaki trombosit konsantrasyonları 2-8 kat artmış olur, dolayısıyla içerdikleri büyüme faktörleri farklıdır27,28. Uygulayıcılar FDA'nın onayladığı ve daha fazla büyüme faktörü elde edilebilen sistemleri tercih etmelidir. TZP hazırlamak için hastadan asit sitrat dekstroz(ACD) içeren antikoagülanlı tüplere venöz kan(antikoagülan/kan oranı: 1/10 olacak) alınır, 10 saniye birbiriyle karışması sağlanacak şekilde çalkalanır. Düşük devirde (3000rpm, 3 dakika) santrifüje edildiğinde tüpte üç kısım ayırt edilir. Alt kısımda eritrositler, orta kısımda buffy coat adı verilen trombosit-lökosit karışımı, en üstte ise plazma bulunur. Buffy coat dikkatlice çekilerek konsantre TZP kullanılabilir veya buffycoat ve üstteki trombositten fakir plazma yeniden 4000 rpm de 3 dakika santrifüje edilince konsantre TZP elde edilmiş olur15. Elde edilen plazma alınan kanın sadece %10'udur.Buna trombin, kalsiyum glukonat veya kalsiyum klorid gibi trombosit agonistleri eklenerek aktive edilir. Böylece trombositler degranüle olur ve büyüme faktörleri ortama verilir. Bu faktörlerin salınması kanın pıhtılaşmasından 10 dakika sonra başlar ve %95'i ilk bir saat içinde salgılanmış olur. Trombositlerin in vivo ömrü yaklaşık 9–10 gündür, oda sıcaklığında belli şartlarla 5 gün saklanabilir ama büyüme faktörü salınmı zaten çok azdır. Santrifüj sırasında, trombositlerin membran stabilizasyonunun korunması ve işlem öncesinde trombosit degranülasyonunun olmaması için düşük G gücü kullanılması çok önemlidir15, 29,30.

    Trombositten zengin plazma topikal veya enjeksiyonla uygulanabilir. Enjeksiyonlar enellikle intradermal veya subdermal olarak yapılmaktadır. Dolgu enjeksiyonu veya mezoterapide uygulanan enjeksiyon teknikleri kullanılabilir. Uygulama tekniği hakkında belli protokoller olmamakla birlikte saçlı deri için; nokta tekniği, deri yenilemede nappaj ve nokta tekniği birlikte, dolgu için de tünel tekniği kullanılabilir. Akne skarlarının tedavisinde önce subcisionyapılıp o alana TZP verilebilir. TZP uygulamalarından sonra belirgin klinik iyileşme 1-2 haftada gözlenir. Maksimum etki için 2-3 hafta ara ile 3-4 uygulama yapılması gerekmektedir18,31.

    TZP kontrendikasyonları

    Trombositopenik, hipofibrinojenemisi, karaciğer hastalığı, malignitesi olan hastalar; akut ve kronik enfeksiyonlarda, hamile ve emzirenlerde, otoimmün hastalığı olanlarda, kan ve kan ürünlerine karşı hassasiyeti olduğu bilinen kişilerde TZP kullanımından kaçınılmalıdır32.

    TZP yan etkileri

    TZP uygulamasında yan etki görülme riski hastanın kendi trombositleri kullanıldığı için oldukça düşüktür. Uygulama enjeksiyon yolu ile yapıldığı için; enjektörün deriye giriş tekniğine bağlı olarak bazı lokal yan etkiler görülebilir. Enjeksiyon yerinde oluşabilen ekimozlar, küçük çaplı olup birkaç gün içersinde tedaviye gerek olmadan iyileşir. Uygulama sırasında oluşan kızarıklık da tedavi gerekmeksizin 30-40 dk'da kendiliğinden kaybolur. Uygulama sonrasında deride hissedilen gerilme hissi 1-2 saat içersinde kaybolur. TZP uygulamasında hastanın kendi kanı kullanıldığı için herhangi bir alerjik reaksiyon görülmesi söz konusu değildir.

    Sonuç olarak TZP pratik bir yöntem olup ciddi yan etkilerinin olmaması, yaygın skar dokusu oluşturmaması, malign transformasyonlara sebep olmaması, kolay bulunabilir ve ucuz elde edilebilir olması alternatif tedavi yöntemi olarak ilgi çekmektedir. Bununla birlikte geniş serili klinik ve fibroblastlar üzerindeki etkilerini doğrulayan deneysel çalışmalarla bu bulguların desteklenmesine ihtiyaç vardır.

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    Tablo 1. TZP'nin Dermatolojik Kullanım Alanları

    Kronik deri ülseri

    Kırışıklık giderilmesi, deri gençleştirme

    Akne skarları

    Alopesi

    Melasma

    Ablatif lazer, kimyasal peeling, roller uygulamalarında yara

    iyileşmesini arttırmak ve hızlandırmak için

    ___________________________________________________

  • Anti-interleukin-1 treatment in 26 patients with refractory familial mediterranean fever

    Objective: To investigate the effect of anti-interleukin-1 (anti-IL-1) treatment on the frequency and severity of attacks and other disease-related clinical parameters and to evaluate the adverse effects associated with anti-IL-1 treatment in 26 patients with refractory familial mediterranean fever (FMF). Methods: The study included 26 FMF patients followed up in our centre using colchicine for 4 months to 30 years. The treatment was switched to anti-IL-1 treatment for various reasons; 20 cases were resistant to colchicine, 8 were intolerant to colchicine, and 3 had prolonged arthritis under colchicine. Clinical response was monitored through the number of attacks, and laboratory inflammation was monitored through erythrocyte sedimentation rate, C-reactive protein, and serum amyloid A concentrations. Colchicine resistance was defined as at least two attacks/month together with C-reactive protein and serum amyloid A levels above the normal range between attacks. The colchicine dose was increased to 2 mg/day before they were considered colchicine-resistant. Results: 24 patients used anakinra (100 mg/day), and 2 used canakinumab (150 mg/month), for –36 months. Sixteen patients with colchicine resistance had no attacks under anti-IL-1 treatment, and 4 had decreased frequency and duration of attacks. Seven of 8 patients intolerant to colchicine used anakinra, and 6 were attack-free under treatment, while 1 using canakinumab had attacks under treatment. One patient with prolonged arthritis used canakinumab but arthritis showed progression and the treatment was changed to IL-6 inhibitor. Three patients had injection site erythema and one had fatigue with anti-IL-1 treatment. Topical steroids with systemic antihistaminics were sufficient for symptom control in two cases, but canakinumab treatment was given due to severe injection site erythema in one case. Conclusion: Anti-IL-1 agents are rational treatment modalities in patients resistant or intolerant to colchicine. Anti-IL-1 agents can control FMF attacks quite effectively and they have a promising role in the treatment of FMF.

  • Association between single nucleotide polymorphisms in prospective genes and susceptibility to ankylosing spondylitis and inflammatory bowel disease in a single centre in turkey

    Background/Aims: To establish the prevalence of the single nucleotide polymorphisms (SNPs) of endoplasmic reticulum aminopeptidase 1 (ERAP1), IL-23 receptor (IL-23R), signal transducer and activator of transcription 3 (STAT-3) and Janus kinase 2 (JAK-2) in ankylosing spondylitis (AS) and inflammatory bowel disease (IBD) in a Turkish population. Materials and Methods: A total of 562 subjects who presented at the Ankara University internal medicine departments of rheumatology and gastroenterology outpatient clinics were recruited in this study, including 365 patients with AS, 197 patients with IBD and 230 healthy controls. ERAP1, IL-23R, STAT-3 and JAK-2) were genotyped in competitive allele-specific polymerase chain reactions. Results: The ERAP1 (rs26653) polymorphism was found to increase the disease risk in patients with AS and IBD compared with the control group (p=0.02 and p=0.01, respectively). In addition, this polymorphism revealed a significant relationship with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Bath AS Functional Index (BASFI) in patients with AS (r=0.829, p<0.001 and r=0.731, p<0.001, respectively). Conclusion: The ERAP1 gene polymorphism might be a risk factor in the pathogenesis of AS and IBD. In contrast, IL-23R gene polymorphisms may serve a protective role in AS and IBD

  • Comparative analysis of patients hospitalized for severe transaminase elevation according to etiology and laboratory findings

    Objective: The aim of this study is to investigate the etiological, epidemiological, clinical and laboratory findings of patients hospitalized in internal clinics with elevated transaminases and to create a point of view with clinical cues for acute hepatitis.

    Methods: A total of 102 patients who were hospitalized in Internal Medicine and Infectious Diseases Clinics between January 2010 and September 2013 and whose transaminase levels were at least five times higher than the upper limit were included in the study. Patients’ age, sex, etiology, laboratory findings, length of stay in the clinic, and duration of liver enzymes normalizations were examined retrospectively. ANOVA, Kruskal-Wallis and chi-square tests were used in the analysis of qualitative and quantitative data.

    Results: Of the 102 patients with acute liver injury, 58 (56.9%) were female and 44 (43.1%) were male. The average age is 46 years. The study group consisted of three main groups: toxic hepatitis (34.3%), acute viral hepatitis (25.5%) and ischemic hepatitis (17.6%). This was followed by acute nonbiliary pancreatitis (6.9%), autoimmune hepatitis (4.9%) and other (10.8%) groups. Transaminase and bilirubin values ​​were higher in acute viral hepatitis than other groups. Acute viral hepatitis group hospitalized for the longest time. The group which the liver enzymes recovered at the latest was toxic hepatitis. The two most common causes of toxic hepatitis were nonsteroidal anti-inflammatory drugs and herbal products. In the ischemic hepatitis group, the mean age was significantly higher. Alcohol use was not effective on the duration of hospitalization and normalization of liver enzymes.

    Conclusion: Rapid determination of etiology, shortening hospitalization periot, and proper use of laboratory tests are important in patients with elevated transaminases. The purpose of this study is to enable the clinician to have an effective approach to acute liver damage.

  • Simultaneously occurred pleural and pericardial effusion related to dasatinib treatment: a case report

    Dasatinib is a proven potent tyrosine kinase inhibitor which is used in the newly diagnosed Philadelphia Chromosome (Ph1) positive chronic myeloid leukemia (CML) treatment when there is no hematological and/or cytogenetic response to imatinib treatment. Pleural and pericardial effusions due to dasatinib therapy may be seen 5 to 30 weeks after the onset of the treatment, but may also develop at any time interval. Pleural effusions are frequently bilateral and exudative, and lymphocyte cell dominance is often observed. It has been observed that when dasatinib treatment is stopped, the side effects which occurred with the treatment are greatly regressed. In this article, we present a case with New York Heart Association (NYHA) functional class III dyspnea under the treatment of dasatinib and developed simultaneous pleural and pericardial effusion, which is rare in the literature. Our aim of presenting this case is to emphasize once again the rarity of simultaneous pleural and pericardial effusion development in dasatinib therapy, and the importance of intermittent cardiopulmonary evaluation before and during the treatment of CML patients.

  • Comparison of three different creatinine clearance calculation methods in patients with type 2 diabetes mellitus(tip 2 diyabetik bireylerde kreatinin klirensini hesaplamada kullanılan üç farklı yöntemin karşılaştırılması)

    Abstract

    Aim: To determine the most accurate and useful method for calculating creatinine clearance by comparing the results of different methods.

    Methods: One hundred type 2 diabetic patients who have been followed by Okmeydani Training and Research Hospital internal medicine and/or diabetes outpatient clinics were included in this study. Individuals with hypertension, acute kidney disease and renal transplantation were excluded from the study.

    Results: Glomerular filtration rate (GFR) calculated with Cockcroft-Gault formula was significantly affected by creatinine, weight,and age (p < 0,050). GFR measured with Modification of Diet in Renal Disease (MDRD) formula was significantly affected by creatinine and age (p < 0,050) in a univariate model; in a multivariate model, this was significantly independently affected by creatinine (p < 0,050). GFR measured with 24h urine was significantly affected by creatinine, weight,and age (p < 0,050) in a univariate model; in a multivariate model, this was significantly independently affected by weight (p < 0,050).

    Conclusion: In this study, those three methods revealed similar results. All of three methods can be used for evaluating renal functions in Type II diabetic patients but creatinine clearance with 24 hours urine method requires two patient visits in a row and a more complex biochemistry laboratory; so in our opinion, this method may be used as an alternative to the other two methods.

    Keywords: Creatinine clearance, Glomerular filtration rate, Type 2 Diabetes

    Öz

    Amaç: Diyabetik bireyler için kullanılabilecek en uygun kreatinin klirensi hesaplama metodunu belirlemek amaçlandı.

    Yöntem: Çalışmaya Okmeydanı Eğitim Araştırma Hastanesi iç hastalıkları ve diyabet polikliniklerine başvurmuş 100 tip 2 diyabetik hasta dahil edildi. Hipertansiyon, akut böbrek yetersizliği tanısı almış veya böbrek nakil alıcısı olan diyabetik hastalar çalışma dışı bırakıldı.

    Bulgular: Cockcroft-Gault değerini kestirmede tek ve çok değişkenli modellerde yaş, ağırlık, kreatininin anlamlı (p < 0,050) etkisi gözlenmiştir. MDRD değerini kestirmede tek değişkenli modelde yaş, kreatininin; çok değişkenli modelde ise yalnızca kreatininin anlamlı bağımsız (p < 0,050) etkisi gözlenmiştir.24 saatlik idrarda kreatinin klirensi değerini kestirmede tek değişkenli modelde yaş, ağırlık, kreatinin değerinin anlamlı (p < 0,050) etkisi gözlenmişken; çok değişkenli modelde ise yalnızca ağırlık değerinin anlamlı bağımsız (p < 0,050) etkisi gözlenmiştir.

    Sonuç: Bu çalışmada üç yöntem de birbirleriyle uyumlu sonuç verdi. Tip II diyabetik hastalarda böbrek fonksiyonlarını değerlendirmek için üç yöntemin tamamı kullanılabilir, ancak 24 saatlik idrar yöntemiyle kreatinin klirensi, üst üste iki hasta ziyareti ve daha karmaşık bir biyokimya laboratuvarı gerektirir; bizim görüşümüze göre, bu yöntem diğer iki yönteme alternatif olarak kullanılabilir.

    Anahtar kelimeler: Glomeruler fitrasyon hızı, Kreatinin klirensi, Tip 2 Diyabet

    Introduction

    Diabetes mellitus (DM) is a chronical and progressive disease. Approximately 150 million people are suffering from this disease and predicted the number for 2025 is 300 million [1,2].

    Morbidity and mortality due to DM and its complications are increasing as the prevalence of type II DM increases [3]. Consequently, early diagnosis and effective treatment of type II DM is needed more and more every day. There are approximately 2.6 million type II DM patients in our country, and it is predicted that at least one-third of 1.8 million people still in impaired glucose tolerance stage will join to this group in the near future [4].

    Diabetic nephropathy (DN) is a serious health problem causing end-stage renal failure. In the United States of America, DN causes 40 % of newly developed end-stage renal failure. DN defined as positive urine albumin stick test or excretion of albumin more than 300 mg in a diabetic patient who is not suffering from other renal diseases. DN, as appears a late finding of diabetes has some physiological, pathological and clinical symptoms. That made some researchers consider DN into stages [5].

    Creatinine clearance measurement is the most common method for evaluating renal functions. Creatinine clearance may be measured with 24-hour urine collection and also with Cockcroft-Gault formula and MDRD.

    In this study, we aimed to to determine the most accurate and useful method for calculating creatinine clearance by comparing the results of different methods. It was aimed to improve feasibility by determining the most suitable method to be possible.

    Materials and Methods

    This retrospective study approved by Okmeydani Training and Research Hospital (OEAH) Clinical Researchs Ethical Board Presidency with a number of 178 at 09.09.2014. Files of type 2 DM patients who applied to one of internal medicine outpatient clinics between 2012 and 2014 were retrospectively screened. From a total of 184 patients; patients with hypertension (n=74), acute renal failure (n=6) or renal transplantion (n=4) were excluded from the study. The remaining 100 patients (56 female, 44 male) included to the case group. Median age of the patients was 56 years with a range from 20 to 82 years.

    Patients’ characteristics (age, gender and weight (kilograms)) and laboratory findings (serum creatinine level (mg/dl), fasting blood glucose (mg/dl), postprandial blood glucose (mg/dl), HbA1c (%) and 24-hour urine creatinine clearance (GFR24) (mg/24 hours)) were evaluated. Roche-Hitachi Cobas 8000 (Serial number: 1349-09, 2014,Japan) was used to evaluate laboratory findings. The prediction of creatinine clearance (in ml/min) by the Cockcroft-Gault formula (GFRC&G) was calculated as (140 − age) × body weight/plasma creatinine × 72 (× 0.85 if female) [6]. The abbreviated MDRD (GFRMDRD) estimate of the kidney function was calculated as 175 × plasma creatinine−1.154 × age−0.203 (× 0.742 if female) [7]. Grading of the patients with regard to renal failure were performed according to the KDIGO 2017 guideline using GFR values (G1-G5) (Table 1) [8].

    IBM SPSS for Windows 21.0 (Armonk, New York, USA) statistics package program was used for analyzes. Mean, median, minimum, maximum, frequency values and standard deviation were used for defining statistics of data. Distribution of the variables was controlled with Kolmogorov Simirnov test. Unpaired t-test and Mann-Whitney U test were used for quantitative data analysis. Chi-square test was used for qualitative data analysis. Spearman correlation test was used for correlation analysis. Univariate and multivariate regression tests were performed. Level of significance determined as p≤0.050 for all analyzes.

    Results

    A total of 100 patients were staged by GFR. Sixty-nine patients (69%) had GFR greater than 90 mL/min. staged as G1, 22 patients (22%) had GFR between 60-89 mL/min staged as G2 and 9 patients (9%) had GFR between 30-59 mL/min staged as G3. None of the patients staged as G4 and G5.

    Creatinine clearance of the patients was calculated by Cockcroft-Gault formula (GFRC&G), Modification of Diet in Renal Disease (GFRMDRD) and 24h urine collection method (GFR24).

    Mean ± Standart Deviation values of these three methods were; GFR24:96.4 ± 28.8 mL/min, GFRC&G:104.5± 29.8 mL/min, GFRMDRD:86.2± 24.7 mL/min .

    Table 2 shows statistical values of patients’ in terms of gender, weight, fasting blood glucose, postprandial blood glucose, HbA1c, GFR24, GFRC&G and GFRMDRD (Table 2).

    Significant (p < 0,050) negative correlation was observed between creatinine levels and GFRC&G, GFRMDRD, GFR24. Significant (p < 0,050) positive correlation was observed betweenGFRC&G, GFRMDRD and GFR24. Significant (p < 0,050) positive correlation revealed between fasting blood glucose, postprandial blood glucose and HbA1c. (Table3)

    In both univariate and multivariate models age, weight, and creatinine had significant (p < 0,050) association on determining GFRC&G value (Table 4). Although in a univariate model age and creatinine had significant (p < 0,050) association on determining GFRMDRD value; in a multivariate model only creatinine had independently significant (p < 0,050) association (Table 5). Although in a univariate model age, weight and creatinine had significant (p < 0,050) association on determining GFR24 value; in a multivariate model only weight had independently significant (p < 0,050) association on determining GFR24 value (Table 6).

    Discussion

    The incidence of DN is increasing in proportion to DM incidence and increased lifetime in diabetics. Our study showed that 73% of patients had GFR under 120 mL/min. However, in our study, there was no significant correlation between fasting blood glucose, postprandial blood glucose and HbA1c and GFR values ​​measured by three different methods.

    This study compared the most popular three methods for calculating creatinine clearance. One of those methods, Cockcroft & Gault formulation uses serum creatinine, age, weight, and gender to calculate creatinine clearance by the unit ml/min [6].The second one is MDRD formulation uses race, age, serum creatinine and gender [7]. The last method is to evaluate the creatinine level in urine patient collected for 24 hours without interruption.

    A study compared Cockcroft & Gault formulation, and MDRD formulation suggested that Cockcroft & Gault formulation calculated the lowest creatinine clearance in patients above age 70; while MDRD formulation is the most valuable method to estimate mortality rate in patients above age 85 [9]. In this study, the median age was under 70. GFRMDRD was slightly lower than GFRC&G without statistical signification. Yet another study published in 2007 suggested that Cockcroft&Gault formulation achieved more accurate results than other methods [10]. Another study published in 2010 suggested that Cockcroft&Gault formulation is superior to the MDRD formulation in patients with normal creatinine clearance and diabetics with normal or close to normal GFR. Otherwise, MDRD formulation had more accurate results [11].

    Our study revealed serum creatinine levels are increasing with age. Yet increased age resulted with lower GFRC&G, GFRMDRD, and GFR24h. Those results pointed out that age may be a prognostic factor for diabetic nephropathy. A study published at 2002 including 98.688 patients age between 20 and 94 years showed progressively increasing serum creatinine levels in male patients from age 60 and female patients from age 40 [12]; results of our study are consistent with this study.

    In our study, independent factors that significantly affected GFRC&G increase are age, weight and serum creatinine. This result was expected as they all are variables in the Cockroft-Gault formulation. This result is consistent with the findings of two other studies. [13, 14]; and being in association with weight, is seemed to be the weakness of Cockroft-Gault formulation. Because of this deficit, another study recommended of estimating a CrCl range with the lower boundary defined by using ideal body weight in the Cockcroft-Gault equation and the upper boundary by using total body weight [15].

    Independent factors significantly affected GFRMDRD increase are age and serum creatinine. This is consistent with the previous studies [13, 16]. This result was expected as they are also variables in the MDRD formulation. It is not surprising that there is no effect of weight on the GFRMDRD since the MDRD formula does not use weight.

    Independent factors significantly affected GFR24h increase are age, weight, and serum creatinine. As creatinine is released from the muscles and muscles are the big part of our weight; weight should be considered normal to affect the GFR24h.

    An increase in GFR24h had a positive correlation with GFRMDRD and GFRC&G. This result indicated these three methods are consistent among themselves.

    Major limitations of this study are being retrospective and the small sample size: Because of the retrospective design of the study some important clinical features could not be recorded. The small sample size may have limited our ability to detect statistically significant results.

    In conclusion, there was no statistically significant difference between Cockcroft-Gault formulation, MDRD formulation and creatinine clearance with 24 hours urine method; they are all equally useful in clinical practice. So all of three methods can be used for evaluating renal functions in Type II diabetic patients but creatinine clearance with 24 hours urine method requires two patient visits in a row and a more complex biochemistry laboratory, and it might give incorrect results because of lack of communication between physician-patient-laboratory triangles especially in an outpatient clinic. In our opinion, this method may remain in the background as a result of the process.

  • Soluble cd40 ligand, soluble p-selectin and von willebrand factor levels in subjects with prediabetes: the impact of metabolic syndrome.

    Clin Biochem. 2012 Jan;45(1-2):92-5. doi: 10.1016/j.clinbiochem.2011.10.022. Epub 2011 Nov 7.

    Soluble CD40 ligand, soluble P-selectin and von Willebrand factor levels in subjects with prediabetes: the impact of metabolic syndrome.

    Genc H1, Dogru T, Tapan S, Tasci I, Bozoglu E, Gok M, Aslan F, Celebi G, Erdem G, Avcu F, Ural AU, Sonmez A.

    Author information

    Abstract

    OBJECTIVES:

    The data regarding circulating levels of markers of platelet activation and endothelial function in people with prediabetes are scant. The aim of the present study was to search blood levels of soluble CD40 ligand (sCD40L), soluble P-selectin (sP-sel) and von Willebrand Factor (vWF) in subjects with prediabetes, along with the effects of the metabolic syndrome (MetS) on these markers.

    DESIGN AND METHODS:

    A total of 77 prediabetic individuals and 81 age, sex and body mass index matched healthy subjects with normal glucose tolerance (NGT) were prospectively analyzed. Anthropometric parameters, fasting plasma glucose, blood d lipid profiles and insulin resistance indexes were determined. Plasma sCD40L, sP-sel and vWF levels were measured by ELISA.

    RESULTS:

    sCD40L, sP-sel and vWF levels in the prediabetic group were similar to those in the controls. However, prediabetic subjects with the MetS had significantly higher level of sCD40L compared to those without MetS. Moreover, sCD40L level correlated significantly with waist circumference, systolic blood pressure and HDL-cholesterol level in the patient group.

    CONCLUSION:

    These data imply that MetS may contribute, at least in part, to the mechanism of platelet activation and endothelial dysfunction in people with prediabetes.

    Crown Copyright © 2011. Published by Elsevier Inc. All rights reserved.

    PMID:

    22100896

    DOI:

    10.1016/j.clinbiochem.2011.10.022

  • Insulin resistance but not visceral adiposity ındex ıs associated with liver fibrosis in nondiabetic subjects with nonalcoholic fatty liver disease.

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    Metab Syndr Relat Disord. 2015 Sep;13(7):319-25. doi: 10.1089/met.2015.0018. Epub 2015 May 26.

    Insulin Resistance but Not Visceral Adiposity Index Is Associated with Liver Fibrosis in Nondiabetic Subjects with Nonalcoholic Fatty Liver Disease.

    Ercin CN1, Dogru T1, Genc H2, Celebi G1, Aslan F3, Gurel H1, Kara M4, Sertoglu E5, Tapan S6, Bagci S1, Rizzo M7, Sonmez A8.

    Author information

    Abstract

    BACKGROUND:

    Nonalcoholic fatty liver disease (NAFLD) is associated with obesity, type 2 diabetes mellitus, and dyslipidemia. It is well known that the presence of visceral fat increases the risk for metabolic complications of obesity, especially NAFLD. The visceral adiposity index (VAI), a novel marker of visceral fat dysfunction, shows a strong association with insulin resistance and also cardiovascular and cerebrovascular events. However, there is conflicting data regarding the association between VAI and NAFLD. Our aim was to assess the relationship between VAI, insulin resistance, adipocytokines, and liver histology, in nondiabetic subjects with NAFLD.

    METHODS:

    A total of 215 male patients with biopsy-proven NAFLD were included. Among this group, serum levels of adiponectin, tumor necrosis factor-α (TNF-α, interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hsCRP) were measured in 101 patients whose blood samples were available.

    RESULTS:

    High gamma-glutamyl transferase (GGT), high total cholesterol (TC), high triglycerides (TGs), low high-density lipoprotein cholesterol (HDL-C), and presence of metabolic syndrome were significantly associated with higher VAI, although only higher GGT and TC were independent factors on multiple linear regression analysis. On the other hand, no significant association was found between VAI and adiponectin, TNF-α, IL-6, and hsCRP levels. The multivariate analysis of variables in patients with (n=124) and without (n=91) fibrosis showed that only higher homeostasis model assessment of insulin resistance value was independently associated with liver fibrosis.

    CONCLUSIONS:

    Our findings suggest that VAI is not related to the severity of hepatic inflammation or fibrosis in nondiabetic patients with NAFLD. The lack of association between the adipocytokines and VAI also implies that the VAI may not be a significant indictor of the adipocyte functions.

    PMID:

    26011302

    DOI:

    10.1089/met.2015.0018

  • The relationship of circulating fetuin-a with liver histology and biomarkers of systemic inflammation in nondiabetic subjects with nonalcoholic fatty liver disease.

    audi J Gastroenterol. 2015 May-Jun;21(3):139-45. doi: 10.4103/1319-3767.157556.

    The relationship of circulating fetuin-a with liver histology and biomarkers of systemic inflammation in nondiabetic subjects with nonalcoholic fatty liver disease.

    Celebi G1, Genc H, Gurel H, Sertoglu E, Kara M, Tapan S, Acikel C, Karslioglu Y, Ercin CN, Dogru T.

    Author information

    Abstract

    BACKGROUND/AIMS:

    Fetuin-A, a glycoprotein with anti-inflammatory properties, plays an important role in counter-regulating inflammatory responses. It has also been associated with insulin resistance and metabolic syndrome. We aimed to investigate circulating concentrations of fetuin-A and its possible association with hepatic and systemic inflammation in nondiabetic subjects with nonalcoholic fatty liver disease (NAFLD).

    PATIENTS AND METHODS:

    We included 105 nondiabetic male subjects with NAFLD [nonalcoholic steatohepatitis (NASH, n = 86) and simple steatosis (SS, n = 19)]. Plasma levels of fetuin-A and markers of inflammation [high-sensitive C reactive protein (hsCRP), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and adiponectin] were measured by enzyme-linked immunosorbent assay method. Insulin sensitivity was determined by homeostasis model assessment of insulin resistance (HOMA-IR) index.

    RESULTS:

    Fetuin-A was negatively correlated with age (r = -0.27, P = 0.006), however there was no association between fetuin-A and body mass index, waist circumference (WC), glucose, insulin, HOMA-IR, lipid parameters, and inflammatory markers. In addition, no significant association was observed between fetuin-A and histological findings including liver fibrosis.

    CONCLUSION:

    This study demonstrated that plasma fetuin-A levels are not correlated with the hepatic histology and systemic markers of inflammation in nondiabetic subjects with NAFLD. Our data also suggested that age is significantly associated with fetuin-A in this clinically relevant condition.

    PMID:

    26021772

    PMCID:

    PMC4455143

    DOI:

    10.4103/1319-3767.157556

    [Indexed for MEDLINE]

    Free PMC Article

  • Neutrophil-to-lymphocyte ratio is not a predictor of liver histology in patients with nonalcoholic fatty liver disease.

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    Eur J Gastroenterol Hepatol. 2015 Oct;27(10):1144-8. doi: 10.1097/MEG.0000000000000405.

    Neutrophil-to-lymphocyte ratio is not a predictor of liver histology in patients with nonalcoholic fatty liver disease.

    Kara M1, Dogru T, Genc H, Sertoglu E, Celebi G, Gurel H, Kayadibi H, Cicek AF, Ercin CN, Sonmez A.

    Author information

    Abstract

    OBJECTIVES:

    It has been reported that the neutrophil-to-lymphocyte ratio (NLR) can be measured relatively easily and can serve as a valuable index for much clinical pathology. The aim of this study was to investigate the association between NLR and hepatic histological findings in patients with nonalcoholic fatty liver disease (NAFLD).

    DESIGN AND METHODS:

    A total of 226 consecutive patients with biopsy-proven NAFLD [nonalcoholic steatohepatitis (NASH, n=105), borderline-NASH (n=74), and simple steatosis (n=47)] were enrolled. NASH and fibrosis were diagnosed histologically using the NAFLD Clinical Research Network criteria.

    RESULTS:

    Significant differences were found in aspartate aminotransferase (P<0.001), alanine aminotransferase (P<0.001) levels, and white blood cell (P=0.007) and neutrophil counts (P=0.042) between the three groups of patients. In addition, significantly higher BMI (P=0.024), waist circumference (P=0.011), aspartate aminotransferase (P=0.003), alanine aminotransferase (P=0.005), insulin (P=0.008), and homeostasis model assessment-insulin resistance (P=0.009) levels were found in patients with fibrosis (n=133) in comparison with those without fibrosis (n=93). There was no correlation between NLR and glucose, homeostasis model assessment-insulin resistance, lipid parameters, and the NAFLD activity score. Analysis of the NLR in relation to histological findings also showed no association between these parameters.

    CONCLUSION:

    To the best of our knowledge, this is the largest study that has investigated these relationships in this clinically relevant condition. The findings of the present study show that NLR is not associated with the severity of hepatic inflammation or fibrosis and thus cannot be recommended as a surrogate marker of liver injury in patients with NAFLD.

    Comment in

    Neutrophil-to-lymphocyte ratio for predicting fibrosis in nonalcoholic fatty liver disease. [Eur J Gastroenterol Hepatol. 2015]

    PMID:

    26062078

    DOI:

    10.1097/MEG.0000000000000405

    [Indexed for MEDLINE]