Current Medicinal Chemistry - Volume 23, Issue 19, 2016

The purpose of this review is to summarize current data on the role of immunosuppressants in the pathogenesis of hypertension and the efficacy and tolerability of major antihypertensive classes in kidney transplant recipients. Arterial hypertension is a common complication after kidney transplantation and a major risk factor for adverse outcome and graft rejection due to blood pressure elevation by immunosuppressive medications. Calcineurin inhibitors induce hypertension by a mechanism related to the imbalance of vasoactive substances endothelin and nitric oxide, and probably by causing overactivity of thiazide-sensitive sodium-chloride-cotransporter. Corticosteroids are well known for their hypertensive effects. The interactions of calcineurin inhibitors and mammalian target of rapamycin inhibitor sirolimus also promote hypertension. Management of arterial hypertension is a complex problem in the care of kidney transplant recipients. Target blood pressure values of <130/80 mm Hg are suggested by the National Kidney Foundation/ Kidney Disease Outcomes Quality Initiative. Calcium channel blockers may be useful in antagonizing the vasoconstrictive effects of calcineurin inhibitors. The renin-angiotensin system inhibitors seem a good option, especially in patients with proteinuria, however their effects on long-term graft and patient survival are controversial. β-Blockers could be beneficial in patients with coronary heart disease, but caution is required due to metabolic adverse effects. Thiazide diuretics could be the reasonable option for patients with glomerular filtration rate ≥30 mL/min/1.73 m2, also with caution regarding hypokalemia and glycemia. Until more evidence is provided, the choice of optimal antihypertensive therapy in kidney transplant recipients should be based on previous individual antihypertensive tolerability and efficacy, comorbidities, concomitant medications and post-transplant kidney function.

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for the treatment of pain, inflamation and fever. They are usually well tolerated in healthy persons, but in patients with risk factors (advanced age, renal impairment, heart failure, liver disease, concurrent medications with antihypertensive drugs), NSAIDs can induce serious renal adverse effects. They include sodium and water retention with edema, worsening of heart failure, hypertension, hyponatremia, hyperkalemia, acute kidney injury, chronic kidney disease, renal papillary necrosis and acute interstitial nephritis. The majority of these adverse effects are due to the inhibition of prostaglandins synthesis and they are dose and duration-dependent. Acute forms of kidney injuries are transient and often reversible upon drug withdrawal. Chronic use of NSAIDs in some patients may result in chronic kidney disease. It is recommended that patients at risk should have preventative strategies in place, including the use of the “lowest effective dose” of NSAID for the “shortest possible time” and monitoring renal function, fluid retention and electrolyte abnormalities. Patients who are taking antihypertensive medications should be monitored for high blood pressure and the doses of antihypertensive medications should be adjusted if needed. In general, the combination of NSAIDs and angiotensin inhibitors should be avoided. Some other preventive measures are dietary salt restriction, use of topical NSAIDs/non-pharmacological therapies and use of calcium channel blockers for treating hypertension.

Ischemic reperfusion kidney injury (IRKI) is a complex pathophysiological event, which is the most common cause of the acute kidney injury. The key characteristic of IRKI is a reduction in glomerular filtration rate, which implies an underlying impairment in hemodynamic regulation. In recent decades, convincing evidence illuminated the molecular and pathological events in the acute kidney injury, revealing the role of ischemia/reperfusion, oxidative stress, apoptosis, inflammation, fibrosis and changes in gene expression which activate different signaling pathways. The cascade of inflammation events is a key mediator of IRKI, which includes the inflammation process, complement activation and mobilization of innate immunity. Oxidative stress represents the increased presence of various free radicals that cannot be buffered by the antioxidant capacity which comprises of enzymatic and non-enzymatic components. Renal tissue injury during ischemia/reperfusion comes as a result of membrane lipids peroxidation, oxidative damage of proteins and DNA and results in apoptosis and necrosis. It is evident from many studies that augmentation of the antioxidant defense mechanisms has a protective role on kidney tissue. In recent years, the importance of heat-shock proteins and MicroRNAs in the pathogenesis of IRKI has been revealed and there are promising indications that in future they could serve as diagnostic biomarkers or therapeutic targets. Striking changes in global gene expression were shown, providing a great potential for fundamental understanding and clinical management of IRKI. The clinical outcome among patients with kidney transplantation will have the furthermost advance from the better understanding of the underlying molecular pathology of IRKI.

Despite the recent findings concerning pathogenesis and novel therapeutic strategies, the mortality rate in patients with acute kidney injury (AKI) remains very high. Early detection of patients with impaired renal function may help to ensure more aggresive treatment and to improve clinical outcome. Serum creatinine is still gold standard of kidney injury, although it is well known as an insensitive and unreliable biomarker (for example, its concentration does not increase significantly until about half of the kidney function is lost). Considering these data, researches and clinicians are making great efforts in the past decade in order to discover and validate novel AKI biomarkers. Kidney injury molecule-1 (KIM-1), Neutrophil gelatinase-associated lipocalin (NGAL), Interleukin-18 (IL-18), Cystatin C (Cys-C) are some of new, promising markers of kidney damage which are currently in the focus of preclinical and clinical studies. Recent data suggest that some of these new biomarkers represent important parametars of acute tubular necrosis (ATN) and reliable predictors of development and prognosis of AKI. Beside that, monitoring of these markers could have significant importance for early diagnosis and clinical course, not only in patients with various forms of AKI and other renal diseases, but also in patients with cardiorenal syndrome, heart failure, cardiopulmonary bypass, cardiothoracical surgical interventions, in the pediatric emergency setting etc. The aim of this review is to summarize the literature data concerning some new biomarkers, evaluate their role as well as their limitations in the early diagnosis and predict clinical outcome of some renal diseases.

Immunosuppressive therapy is the cornerstone of successful kidney transplantation. Frequently used immunosuppressives are cyclosporine, tacrolimus, sirolimus and mycophenolic acid. These drugs have narrow therapeutic index and show high pharmacokinetic variability. In order to maintain the balance between efficacy and safety, dosing is based on measured drug concentrations. Proper identification, quantification and understanding the sources of variability in measured concentrations facilitate routine dose adjustment in clinical practice. Classical pharmacokinetic studies have limited use in transplant patients attributable to design with intense sampling in a small, relatively homogenous population, and identification of only single variability factor per study. Population approach is a powerful tool for analysing sparse data, identifying factors that influence drug pharmacokinetics and estimating variability. In this report we reviewed available population pharmacokinetic models for cyclosporine, tacrolimus, sirolimus and mycophenolic acid in adult kidney transplant patients. The major focus was to describe various demographic factors, biochemical parameters, genetic polymorphisms of metabolic enzymes and transporters and drug-drug interactions, which have been identified as an important concern of pharmacokinetic variability in kidney transplant patients.

Free radical-mediated injury releases proinflammatory cytokines and activates innate immunity. It has been suggested that the early innate response and the ischemic tissue damage play roles in the development of adaptive responses, which may lead to acute kidney rejection. Various durations of hypothermic kidney storage before transplantation add to ischemic tissue damage. The final stage of ischemic injury occurs during reperfusion that develops hours or days after the initial insult. Repair and regeneration processes occur together with cellular apoptosis, autophagy and necrosis and a favorable outcome is expected if regeneration prevails. Along the entire transplantation time course, there is a great demand for novel immune and nonimmune injury biomarkers. The use of these markers can be of great help in the monitoring of kidney injury in potential kidney donors, where acute kidney damage can be overlooked, in predicting acute transplant dysfunction during the early post-transplant periods, or in predicting chronic changes in long term followup. Numerous investigations have demonstrated that biomarkers that have the highest predictive value in acute kidney injury include NGAL, Cystatin C, KIM-1, IL-18, and L-FABP. Most investigations show that the ideal biomarker to fulfill all the needs in renal transplant has not been identified yet. Although, in many animal models, new biomarkers are emerging for predicting acute and chronic allograft damage, in human allograft analysis they are still not routinely accepted and renal biopsy still remains the gold standard.

Kidney damage can be induced by ischemia, autoimmune diseases, hypertension, allograft rejection, metabolic or genetic disorders, infections or toxins. The influence of these factors could result in acute kidney injury (AKI) defined as an unexpected decrease in urine output or renal function, or encourage the development of chronic kidney disease (CKD). Biomarkers of renal function, measured in urine and serum, are in increasing use in order to estimate the severity and nature of kidney injury, and consequently apply appropriate therapy and improve patient management. The determined values of biomarkers can suggest the potential risk of kidney disease and the type of renal injury, predict the disease progression, as well as be helpful for assessing the response to an applied therapy. Although novel biomarkers are in practical use, serum creatinine, the indicator of glomerular filtration rate is still the most frequently used biomarker of renal function despite its known limitations. In recent decades, numerous studies resulted in discovering urinary and serum proteins that can serve as biomarkers for early and accurate detection of AKI and its development, as well as the identification of CKD. This review gives an overview of the most important renal biomarkers investigated in kidney diseases, classified in following types: functional biomarkers, up-regulated proteins, enzymes, and cycle arrest biomarkers. It describes their properties, physiological roles, and discusses the utility of these molecules in different clinical settings.

Acute renal failure (ARF) represents a severe complication of malignancies, that causes significant morbidity and mortality. ARF is a common part of multiple organ dysfunction in critically ill patients with cancer with reported mortality rates from 72% to 85% in patients who need renal replacement therapy. The pathways leading to ARF in cancer patients are common to the development of ARF in other conditions. However, certain factors leading to the development of ARF may be associated to the tumor or to the tumor therapy. The purpose of this review is to give specific aspects of renal disease in critically ill cancer patients (CICPs), to overview the causes of ARF in CICPs and to describe recent progress in the management of these complications, including treatment toxicity and bone marrow transplantation (BMT). The prevention of ARF is obligatory and therefore the possible treatments of ARF in CICPs are also discussed.

Endothelial dysfunction is principally characterized by impaired endothelium– dependent transduction mechanisms related to vascular relaxation, as an outcome of decreased release of endothelium–derived relaxing factors, mainly nitric oxide, as well as augmented oxidative stress, increased inflammation and predominance of vascular action produced by endothelium–derived contracting factors. Current data strongly suggest that pathological development of different types of kidney impairment with further progression to renal failure includes notable vascular changes associated with endothelial dysfunction. In accordance, this scientific field represents an advancing area of investigation, involving different biomarkers of endothelial dysfunction linked to renal impairment, as well as clinical findings with new information that can provide a more comprehensive understanding of the role of endothelial dysfunction in kidney disease. With regards to quoted facts, the aim of this article was to review the latest data related to endothelial dysfunction and renal failure by selection of relevant articles released from 2010 to 2015.

Atrial fibrillation (AF) and chronic kidney disease (CKD) are disorders with increasing prevalence. The presence of CKD increases the risk of incident AF and vice versa, and the presence of AF may accelerate CKD progression. Nearly a third of patients with established CKD also have AF, whilst half of AF patients may have some degree of renal dysfunction. Both AF and CKD are associated with increased cardiovascular morbidity and mortality, including significantly increased risk of stroke or systemic embolism. Oral anticoagulant therapy (OAC), either with vitamin K antagonists or with non-vitamin K oral anticoagulants (NOACs) is essential to optimise prevention of stroke and systemic embolism in AF patients with one or more stroke risk factors, and NOACs are more convenient and generally safer than vitamin K antagonists mostly due to consistently reduced risk of intracranial bleeding. The use of OAC must be balanced against the risk of OAC-related bleeding, which depends on the presence of bleeding risk factors. Renal failure is a well-established bleeding risk factor and renal function should be routinely assessed in all patients presenting with AF. Since the risk of bleeding increases in parallel with CKD severity, the clinical decision to use OAC in AF patients with severe CKD may be challenging. In this review article we summarize the OAC agents currently used in clinical practice and discuss the role of NOACs for stroke prevention in patients with AF and CKD.

The kidney has numerous complex interactions with the heart, including shared risk factors (e.g., hypertension, dyslipidemia, etc.) and mutual amplification of morbidity and mortality. Both cardiovascular diseases and chronic kidney disease (CKD) may cause various alterations in cardiovascular system, metabolic homeostasis and autonomic nervous system that may facilitate the occurrence of cardiac arrhythmias. Also, pre-existent or incident cardiac arrhythmias such as atrial fibrillation (AF) may accelerate the progression of CKD. Patients with CKD may experience various cardiac rhythm disturbances including sudden cardiac death. Contemporary management of cardiac arrhythmias includes the use of antiarrhythmic drugs (AADs), catheter ablation and cardiac implantable electronic devices (CIEDs). Importantly, AADs are not used only as the principal treatment strategy, but also as an adjunct therapy in combination with CIEDs, to facilitate their effects or to minimize inappropriate device activation in selected patients. Along with their principal antiarrhythmic effect, AADs may also induce cardiac arrhythmias and the risk for such proarrhythmic effect(s) is particularly increased in patients with reduced left ventricular systolic function or in the setting of electrolyte imbalance. Moreover, CKD itself can induce profound alterations in the pharmacokinetics and pharmacodynamics of many drugs including AADs, thus facilitating the drug accumulation and increased exposure. Hence, the use of AADs in patients with CKD may be challenging. In this review article, we provide an overview of the characteristics of arrhythmogenesis in patients with CKD with special emphasis on the complexity of pharmacokinetics and risk for proarrhythmias when using AADs in patients with cardiac arrhythmias and CKD.