Yavuzer Koza

Acute kidney injury: current concepts and new insights

Abstract: Background: Acute kidney injury, which was previously named as acute renal failure, is a complex clinical disorder and continues to be associated with poor outcomes. It is frequently seen in hospitalized patients, especially in critically ill patients. The primary causes of acute kidney injury are divided into three categories: prerenal, intrinsic renal and postrenal. The definition and staging of acute kidney injury are mainly based on the risk, injury, failure, loss, end-stage kidney disease (RIFLE) criteria and the acute kidney injury network (AKIN) criteria, which have previously been defined. However the clinical utility of these criteria is still uncertain. Several biomarkers such as Cystatin C and neutrophil gelatinase-associated lipocalin have been suggested for the diagnosis, severity classification and most importantly, the modification of outcome in acute kidney injury. Methods: Current literature on the definition, biomarkers, management and epidemiology of acute kidney injury was reviewed by searching keywords in Medline and PubMed databases. Results: The epidemiology, pathophysiology and diagnosis of acute kidney injury were discussed. The clinical implications of novel biomarkers and management of acute kidney injury were also discussed. Conclusions: The current definitions of acute kidney injury are based on the RIFLE, AKIN and KDIGO criteria. Although these criteria have been widely validated, some of limitations are still remain. Since acute kidney injury is common and harmful, all preventive measures should be taken to avoid its occurrence. Currently, there is no a definitive role for novel biomarkers.

Uric acid levels and atrial fibrillation.

We read the article entitled ‘‘Serum uric acid levels are associated with atrial fibrillation in patients with ischemic heart failure’’ by Tekin et al with interest. They evaluated the association between serum uric acid (SUA) and atrial fibrillation (AF) in patients with chronic heart failure (HF). Patients with AF had significantly higher SUA levels, and this was independently associated with AF in patients with ischemic HF. We have some comments about this study. Both AF and HF share common risk factors and frequently coexist. Hypertension is a well-known risk factor for AF. In the Tekin et al study, the number of patients with hypertension in the AF group was low. In addition, there are data to support an association between inflammation and AF. C-reactive protein and fibrinogen are rapid, reliable, and noninvasive tests. The study would be stronger if Tekin et al measured these markers and carried out a correlation analysis between SUA and AF with these markers in their study. Tekin et al did not explain how they defined and measured the SUA levels. Although left atrium (LA) size seems to reflect left ventricular diastolic dysfunction, they could also assess other specific indexes of ventricular diastolic function. Furthermore, they did not provide data on the body mass index (BMI) that is related to the LA size. Uric acid is often elevated in patients with HF. Gotsman et al found that younger age, male gender, diabetes, BMI, urea, reduced glomerular filtration rate, treatment with furosemide, thiazide, spironolactone, b-blocker, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker were predictive of an increased SUA level. Tekin et al did not define the standard medical treatment. Because many drugs can affect SUA levels, it would be useful if the authors provided data about the usage of drug classes other than diuretics. Also, there is no information about the usage of statins in patients with hyperlipidemia, and they did not denote any distinction between the groups for acute or chronic HF.

Coronary fat embolism following subarachnoid hemorrhage: an experimental study

BACKGROUND Subarachnoid hemorrhage (SAH) can lead to neurogenic pulmonary edema (NPE), and chylomicron metabolism may be altered unfavorably in acute lung injury. This study aimed to investigate the possible effect of NPE on the development of coronary fat embolism. METHODS This study was conducted on 27 rabbits, 5 of which were used as the control (n=5). Experimental SAH was induced in 15 of the animals by injecting homologous blood into the cisterna magna, and the remaining 7 animals were administered only isotonic saline solution (Sham, n=7) in the same manner under general anesthesia. After 21 days, all the animals were euthanized, and their hearts, lungs, and brains underwent histopathological examination. RESULTS Six animals died of SAH during the experiment, and foamy hemorrhagic parenchymal lesions and intra-alveolar hemorrhage were observed in their lungs. The histopathologic findings revealed minimal changes in the lungs, heart, and brains of the surviving animals; however, an abundant amount of fat globules was found in the coronary arteries of the six nonsurviving animals. There was a meaningful difference between the number of occluded coronary arteries with fatty globules in the surviving and nonsurviving animals (P<.001). However, the difference between the survivors and the isotonic-saline-injected group was not meaningful (P>.05). Coronary fat embolism was an important mortality factor following SAH (P<.005). CONCLUSIONS In SAH-induced NPE, the leakage of chylomicrons into the systemic circulation may lead to coronary fat embolism, which has not yet been reported in the literature.

Neutrophil–Lympocyte Ratio and Cardiovascular Diseases An Update

The neutrophil–lymphocyte ratio (NLR) has gained significant interest for the prediction of outcomes in patients with vascular disease. The NLR is easily obtained from a full blood count. The NLR is a reflection of the following 2 different yet complementary systems: neutrophils are part the inflammatory response and lymphocytes part of the adaptive immune response. An increased neutrophil count is associated with adverse angiographic outcomes in patients with ST-segment elevation myocardial infarction (STEMI) and peripheral vascular dysfunction in individuals at low cardiovascular risk. Lower lymphocyte counts are associated with adverse outcomes in patients with chronic coronary artery disease (CAD) and heart failure. Horne et al were the first to report the relevance of the NLR in stable CAD. In an average follow-up of 3.5 years, the total white blood cell count was an independent predictor of death/myocardial infarction, but the NLR provided better risk prediction. Recently, Pan et al reported that the NLR was independently correlated with coronary blood flow and was an independent risk factor for in-hospital mortality in patients with STEMI undergoing percutaneous coronary intervention (PCI). In this prospective study, patients were stratified on admission into NLR tertiles. During the 12-month follow-up, a significant increase in long-term mortality was observed in tertiles I to III. Others also reported that the NLR was independently associated with the severity of CAD in patients with STEMI. In another prospective multicenter study, the NLR was an independent predictor of both in-hospital and long-term outcomes among patients with STEMI undergoing primary PCI (pPCI). Similarly, Sen et al found that in patients with STEMI who underwent pPCI, elevated NLRs on admission correlated with both no-reflow phenomenon and long-term prognosis. Cicek et al suggested that the combined use of NLR and platelet–lymphocyte ratio may be useful for the prediction of inhospital and long-term mortality in patients undergoing pPCI. There are some conflicting results on the association between baseline leukocyte profile and prognosis in patients with STEMI. Smit et al showed that the leukocyte profile at baseline was not associated with 1-year mortality. Park et al measured total and differential leukocyte counts once at admission and 24 hours thereafter in patients with STEMI treated with pPCI; they found that the leukocyte profile 24 hours after admission, but not the admission leukocyte profile, was associated with clinical outcomes (all-cause death). Indeed, Chia et al showed that total leukocyte and neutrophil counts at 24 hours after pPCI, but not the baseline hematologic indices, were an independent predictor of adverse cardiac events in patients with STEMI. In contrast, Sulaiman et al reported that admission leukocyte count was an independent risk factor for in-hospital cardiogenic shock and mortality in patients with acute coronary syndrome. In another study, in patients with STEMI, preprocedural high NLR was significantly associated with both stent thrombosis and higher mortality rates. There are no established cutoff values for the NLR. Azab et al reported that patients with non-STEMIs with an average NLR >4.7 had increased mortality. Horne et al proposed an NLR >4.71 as a cutoff value for patients with stable CAD. In the study of Park et al, the cutoff value was 5.44. Those studies have mainly used the highest quartile of NLR as the cutoff value. In contrast, in the Pan et al and Ayca et al studies, the NLR cutoff value for predicting in-hospital mortality was derived from receiver–operating characteristic curve analysis with threshold values of 5.9 and 4.9, respectively. On the other hand, a few studies have reported a higher prevalence of previous PCI in the lowest admission NLR tertile and suggested that anti-inflammatory actions of some medications after PCI, such as clopidogrel and statins, lower the NLR. The NLR has been also associated with contrastinduced nephropathy, which is an emerging important issue in patients receiving contrast media. The NLR, measured at admission, 24 hours after PCI, immediately before PCI and 1, 2, 3, 5, and 30 + 2 days later or calculated as an average or maximum value has been found to be an independent predictor of mortality and adverse outcomes. A study of 692 Chinese patients with STEMI found that the NLR measured at admission, 24, and 72 hours after admission, before discharge, and both maximum and average NLR during hospitalization all predicted mortality. In STEMI, the peripheral leukocyte count usually increases within 2 hours after the onset of chest pain and peaks 2 to 4 days after infarction returning to normal in 1 week. The shorter life span (around 7 hours) with a rapid turnover of

The inconclusive results of the studies on glycoprotein IIIa platelet receptor gene polymorphism and coronary artery disease: an area of darkness.

We read with great interest the article entitled ‘‘Relationship between glycoprotein IIIa platelet receptor gene polymorphism and coronary artery disease’’ by Verdoia et al. The authors investigated whether a single-nucleotide polymorphism of IIIa subunit (Leu 33 platelet antigen 1 and 2 [PlA/PlA]) is associated with the extent of coronary artery disease (CAD) and carotid atherosclerosis. The main finding of this study is that the PlA allele was not associated with the prevalence and extent of CAD and carotid atherosclerosis. The platelet glycoprotein (GP) IIb/IIIa receptor composed of 2 subunits is an essential component of platelet aggregation and plug formation. As Verdoia et al mentioned, in the subunit IIIa, the substitution of a cytosine for a thymidine at position 1565 in exon 2 results in a change in the 33rd position of the amino acid chain (Leu ! Pro). This single-nucleotide polymorphism is responsible for the PlA/PlA, in which the ancestor gene is PlA and the variant gene is PlA. Bottiger et al evaluated the role of human platelet antigen (HPA) 1 and HPA-3 as risk factors for myocardial infarction (MI) and CAD, and this study consisted of a different patient population from Verdoia et al with control groups. Indeed, study of Park et al consisted of patients who had minimal CAD or normal coronary arteries and significant CAD. They found an association between HPA-3 polymorphism and MI. In the present study, the percentage of patients with acute coronary syndrome (ACS) is considerably high. It is well known that ACS and stabile CAD are different disorders, as in ACS, the underlying lesion may be stenotic or nonstenotic and more importantly nonstenotic lesions are far more frequent than stenotic plaques and account for the majority of ruptured culprit plaques. In this context, prevalence or extent of CAD may not give sufficient estimated risk prediction of MI. Indeed, the possibility of pharmacogenomic interaction and a possible effect of medication on atherosclerotic process and clinical events cannot be certainly excluded. In a meta-analysis, the PlA/ PlA variant was significantly associated with aspirin resistance only in healthy individuals. Another study, which included patients with stabil CAD treated with aspirin, demonstrated that GPIIIa PlA/PlA genotype carriers have a significantly increased risk of acute vascular ischemic events associated with a poor prognosis at 1 year. Also, it is important to know whether these polymorphisms alter platelet function or not. Andrioli et al demonstrated that in individuals carrying the PlA allele, there was a significantly lower platelet response through thromboxane A2 pathway compared with PlA/PlA genotype carriers. Lopes et al reported a significant increase in major cardiovascular event incidence in patients with stable CAD who were PlA carriers and smokers. Although Verdoia et al mentioned about the possible reason for association between GPIIIa PlA/PlA gene polymorphism and the development of atherosclerosis, there is no sufficient explanation for their contrasting results. Additionally, we wonder about the scientific reason to consider the vessel that was previously treated by percutaneous coronary intervention and no stenosis as significantly diseased. There may be several reasons for the differences observed between all these studies including the variable prevalence of PlA variant in the different patient populations, influence of ethnic and genetic background, the possible link between PlA polymorphism and other true cardiovascular risk factors (eg, smoking) as in the present study, the possible role of this polymorphism in such a variability of response to either antiplatelet treatment or other drug, some medical conditions that could have a major influence on CAD, and the bias of patient selection and genotype mistyping. In conclusion, further studies are needed to address the relationship between single-nucleotide polymorphism in components of each of the plaque, blood, and myocardial vulnerabilities and future outcomes. As atherosclerosis is a diffuse and multisystem disorder, it is important to recognize the total burden of vulnerable plaques and patients other than the extent of CAD.

Acute decompensated heart failure and pulmonary hypertension.

I read with interest the article entitled “Pulmonary Hypertension, Right Ventricular Function, and Clinical Outcome in Acute Decompensated Heart Failure” by Aronson et al in a recent issue of Journal of Cardiac Failure. The authors reported that in patients with acute decompensated heart failure (ADHF), pulmonary hypertension (PH) and right ventricle function provide incremental prognostic information independently from other established predictors of outcome. I have some additional comments about that study. Systolic blood pressure measured at admission affects mortality during early follow-up and has a significant effect on outcome for at least 5 years. The definition of PH is not based solely on the sum of the peak systolic pressure gradient across the tricuspid valve and the right atrial pressure. It should be evaluated together with tricuspid regurgitation velocity and presence or absence of additional echocardiographic variables. It has been shown that pulmonary arterial pressure (PAP) estimation can be inaccurate with a range of 48%e54% and that PAP may be overor underestimated from the tricuspid regurgitant velocity. Therefore, PH can not be reliably defined by a cutoff value of Doppler-derived PA systolic pressure. In heart failure (HF), chronic medical treatment is associated with demonstrable decreases in left ventricle (LV) size and improvement in LV function. Because patients with advanced chronic HF may have more fibrotic changes and patients with earlier stages of HF may have more reversibility, I wonder about the number of patients with new-onset ADHF in the present study. In another study, a history of HF was one of the strongest independent predictors of 5-year mortality in ADHF. Also, the authors did not give information about the treatment of patients (with, eg, inotropic agents, intravenous diuretics, and vasodilators) in the hospital course. Indeed, treatment of HF in acute settings may have some structural and functional effects that translate into the echocardiographic measurements. In an another study, Ramasubbu et al demonstrated that treatment of ADHF was significantly associated with decreasing in right atrium and right ventricle sizes and inferior vena cava dimensions. Consequently, it is hard to draw such a conclusion from this study as the one the authors suggested.

Can statins alter coronary plaque morphology assessed by intravascular ultrasound

We read with interest the article by Hikita et al entitled ‘‘Impact of Statin Use Before the Onset of Acute Myocardial Infarction on Coronary Plaque Morphology of the Culprit Lesion.’’ They evaluated the impact of statin treatment before the onset of acute myocardial infarction (AMI) on coronary plaque morphology at culprit lesions by using intravascular ultrasound virtual histology (IVUS-VH) before percutaneous coronary intervention (PCI). They concluded that statin use before the onset of AMI might have effects on coronary plaque morphology of the AMI culprit lesion with less necrotic core and greater fibrous and fibrofatty component. Statin therapy, especially intensive doses, is associated with a decreased plaque size, lipid content, and thickness of the fibrous cap. Statins have pleiotropic effects that are independent of lipid-lowering effects. The pleiotropic effects of statins (anti-inflammatory and antithrombotic properties) are often greater with high doses of statins, and there may be individual differences among various statins. A study comparing 8 months of pitavastatin (4 mg daily) with pravastatin (20 mg daily) showed that pitavastatin induced a reduction in fibrous and fibrofatty tissue, but an increase in necrotic core while on pravastatin showed no effects on fibrous tissue and the necrotic core but a decrease in fibrofatty tissue. In the Hikita et al study, the statin doses are low and there is no information about the patients’ medication other than statins and whether there was statin loading before PCI. It would be useful if the authors provided information about the treatment duration of statins. Hikita et al evaluated the impact of statin treatment on coronary plaque morphology only at culprit lesions; it would be useful if they also evaluated nonculprit lesions. A 3-vessel gray-scale IVUS study showed that at least 1 plaque rupture was found somewhere other than at the culprit lesions in 79% of the patients with AMI. The results of the Providing Regional Observation to Study Predictors of Events in Coronary Tree (PROSPECT) trial provided data about the natural history of vulnerable plaques observed by gray-scale IVUS and IVUSVH. In this study, 697 patients with acute coronary syndrome underwent 3-vessel coronary angiography and IVUS study after PCI. At follow-up, recurrent clinical events were equally attributable to the culprit and nonculprit lesions. There have also been some concerns raised about the IVUS-VH because of its poor correlation with necrotic core in a porcine model. Although our goal must be the identification of vulnerable plaques before they rupture, assessment of ruptured plaques provides information regarding plaque vulnerability. Therefore, caution must be taken when drawing conclusions from studies using different IVUS approaches.

The Paradox of Uric Acid in Cardiovascular Diseases

We read the article ‘‘Association Between Uric Acid and Coronary Collateral Circulation in Patients With Stable Coronary Artery Disease’’ by Uysal et al with interest. They investigated the association between serum uric acid (SUA) levels and development of coronary collateral (CC) vessels in patients with stable coronary artery disease (CAD). Higher levels of SUA were associated with poor CC vessels. We have some additional comments. There are some caveats including history of gout and coronary artery bypass grafting as exclusion criteria for no clear reasons, most importantly no control of current medication and a confounding difference in gender. The CC vessels are usually an adaptation to ischemia and shear stress, and they play a role in reducing infarct size, preserving left ventricular function, and increasing survival. The SUA levels are usually lower in premenopausal women compared with men. The SUA levels depend on several variables including dietary purine intake, fructose ingestion, the degradation of endogenous purines as well as renal and intestinal excretion of urate. Also, as the authors have mentioned, several drugs can influence SUA levels (eg, losartan and statins). Uric acid (UA) might have a protective effect against cardiovascular disease (CVD), but studies have reported associations with an increased risk of CAD, higher blood pressure, and adverse CVD risk profile. The Framingham Heart Study reported that UA was not a risk factor for CVD, and that clinical risk evaluation should only be based on the classic risk factors. Recently, Palmer et al investigated the association of plasma UA with CAD and hypertension using Mendelian randomization. They concluded that there is no evidence for a causal association, and that the apparent link is confounded by body weight. In the Multiple Risk Factor Intervention Trial, the association between hyperuricemia and CVD was weak and did not persist when the analysis was limited to men with hyperuricemia without a diagnosis of gout. Except an association with some neurological diseases, low SUA levels are not known cause of any disorder or disease. Questions waiting for answers include does lowering the SUA levels reduce CVD risk? What mechanisms may link SUA and CVD? These issues require well-designed prospective studies with hard end points, such as CVD mortality, myocardial infarction, and stroke. References

Mean Platelet Volume and Acute Coronary Syndrome

We read the article entitled ‘‘The Relationship Between Mean Platelet Volume and Atherosclerosis in Young Patients With ST Elevation Myocardial Infarction’’ by Ozkan et al with interest. The authors concluded that a high mean platelet volume (MPV) can be an independent predictor of acute myocardial infarction (AMI). They also suggested that MPV can be added to the new risk factors for AMI. Patients with nonalcoholic fatty liver disease is associated with higher MPV compared with control individuals. Nadar et al found that among patients with hypertension, regular aspirin treatment was associated with increased MPV. Lifestyle modification, antihypertensive, lipid-lowering, and diet therapies can also affect the MPV. Ozkan et al did not define the MPV reference value. Also, the MPV values of EDTA samples are at least 9% higher than those of citrated samples. There are conflicting results about the effect of aspirin on MPV. Contrary to what has been assumed, aspirin has no effect on platelet size. Therefore, we wonder why Ozkan et al excluded treatment with aspirin in their study. It would be useful if they provide data about the management of patients and draw blood samples in the second and final hospital days. In the Ozkan et al’s study, the patients might be categorized into tertiles according to the admission, MPV value, and platelet count. Bigalke et al reported that low platelet counts were associated with higher expression of glycoprotein VI and elevated inflammatory markers in the acute coronary syndrome. Azab et al found that the MPV/platelet count ratio was superior to MPV alone in predicting long-term mortality after non-STsegment elevation myocardial infarction. Therefore, the use of MPV/platelet ratio might be a reasonable approach. The cross-interaction between platelets and leukocytes has been reported. Ozkan et al could also assess this relationship in their study. We think that it is difficult to attribute risk to a particular MPV value. In a review, Gasparyan et al illustrated that while high-grade inflammatory disorders (eg, active rheumatoid arthritis and ulcerative colitis) were associated with numerous small platelets, low-grade inflammatory disorders (eg, psoriasis and Behcet’s disease) were associated with a large MPV. The diagnostic value of MPV and other platelet indices in thrombotic diseases requires further studies. References

The relationship between neutrophil-to-lymphocyte ratio and coronary artery disease.

applied as a good cardiac biomarker. However, there are many concerns of this biochemical test. First, as it is widely discussed, this biomarker is considered a non specific marker (3). Its increase level can be due to many causes and if there is no good ruling out of other concomitant disease, the application as cardiac marker can lead to misinterpretation. Second, the standardization of the technique is very important. At least, the consensus to develop the international laboratory procedure guideline and reference range setting is needed. Bojesen et al. (4) found that “plasma YKL-40 increases with age within and across healthy individuals from the general population ” and concluded for the necessity of “age-stratified or age-adjusted reference levels”