Patient case: 57-year-old male with melanoma; genetic feature: BRAF (V600E), PTEN loss of function

Clinical trial: Effect of Obstructive Sleep Apnea on Central Blood Pressure and Kidney and Endothelial Function

Summary: Obstructive sleep apnea (OSA) is a frequently underdiagnosed condition that has emerged as an increasing medical problem with important social and financial implications worldwide. OSA is a well established risk factor for systemic hypertension myocardial infarction or stroke and it has been documented that blood pressure rises in a very consistent fashion during apneic episodes. The incidence of the episodes of apnea during sleep causes repeated subclinical acute kidney injuries (AKI) contributing to the development of CKD. One of the mechanisms responsible for AKI might be endothelial injury followed by an increase of central aortic pressure.

Detailed description: Obstructive sleep apnea (OSA) is a frequently underdiagnosed condition that has emerged as an increasing medical problem with important social and financial implications worldwide. Its prevalence may reach 25% in middle-aged men and 11% in women. The most important risk factor for OSA is obesity - every 10% weight gain increases the incidence of the disease 6 times. OSA usually occurs in middle age males and is characterized by history of snoring, daytime somnolence and nocturnal choking or gasping. The underlying cause is transient cessation of airflow due to occlusion of the oropharyngeal tract. Episodes of apnea are considered important if they persist for longer than 10 seconds, but in some cases they may last as long as 2 minutes. The airway occlusion results in recurrent hypoxia, hypercapnia, arousals from sleep, compensatory hyperventilation leading to secondary hypocapnia and generation of exaggerated negative intrathoracic pressure that all can either directly or indirectly be harmful to the cardiovascular system through several pathways like sympathetic activation, inflammation, oxidative stress and endothelial dysfunction. Recurrent episodes of apnea/hypoxia may negatively affect the function of many organs, e.g. they induce (cyclical bradycardia during the apneic episodes, followed by tachycardia during the ensuing ventilatory phases) or rise blood pressure. Moreover, OSA is a well established risk factor for systemic hypertension myocardial infarction or stroke and it has been documented that blood pressure rises in a very consistent fashion during apneic episodes. The mechanisms responsible for this phenomenon are complex because the direct effects of apnea (hypoxemia and low intrathoracic pressure) are modified by cardiopulmonary reflexes. Undoubtedly, the rapid increase in arterial pressure that occurs at the end of an apneic episode is mainly mediated by surges in sympathetic function during the arousal reaction.
  Hypertension has emerged as a second, after diabetes mellitus, most frequent cause of chronic kidney disease (CKD). The rise of arterial blood pressure and endothelial damage due to ischaemia during apneic episodes may contribute to CKD. According to the recent findings OSA patients are much more frequently diagnosed with chronic kidney disease. The high frequency of OSA in patients with renal function impairment could be explained by the fact that the most common comorbid conditions of CKD, namely atherosclerosis and diabetes, are also independently associated with his syndrome. The detailed pathogenesis of the strong relation between OSA and CKD has not been investigated so far.
  OSA patients are characterized by arterial stiffness, evaluated by pulse-wave velocity (PWV). PWV is a sensitive and validated marker of cardiovascular risk, including premature coronary artery disease, atherosclerosis, stroke and cardiovascular mortality.
  The diagnosis of acute kidney injury (AKI) is routinely based on changes in serum creatinine, but its measurements are a poor indicator of acute deterioration in kidney function. First, serum creatinine concentrations might not change until about 50% of kidney function has already been lost. Second, serum creatinine levels can vary widely with age, sex, muscle mass, muscle metabolism, medications and hydration status. Novel, more specific and sensitive biomarkers of AKI are neutrophil gelatinase-associated lipocalin (NGAL), cystatin C, kidney injury molecule 1 (KIM-1), liver-type fatty acid-binding protein (L-FABP), which concentrations in both urine or serum rise significantly in patients with AKI and correlate with severity of kidney injury.
  CKD is a devastating illness that has reached epidemic proportions worldwide. CKD is characterized by a progressive decline in kidney function that is associated with excess morbidity and mortality. The deterioration of kidney function can be delayed and patient outcome favorably affected if kidney disease is recognized and treated in a timely manner.
  In our study we would like to prove that apneic episodes during sleep can cause repeated renal ischaemia-reperfusion injuries, which may lead to repeated acute subclinical kidney injuries (AKI) contributing to the development of chronic kidney disease.
  The aim of this project is to study the influence of sleep apnea syndrome on the markers of acute kidney injury, endothelial function, arterial stiffness and central aortic pressure.

Eligibility: Inclusion Criteria:
  1. Males with high risk of obstructive sleep apnea syndrome as clinically assessed by coincidence of typical symptoms (e.g. daily somnolence, witnessed apnea, non-refreshing sleep), obesity and high score on Epworth sleepiness scale (ESS) with age range from 18 to 70 years
  2. Glomerular filtration rate (MDRD formula-based) > 60 ml/min
  3. Arterial hypertension diagnosed according to the European Society of Hypertension 2007 Guidelines.
  Exclusion Criteria:
  1. Mental illness
  2. Proteinuria >2 g/24h
  3. Acute and chronic inflammation
  4. Heart failure III or IV grade
  5. Uncontrolled diabetes mellitus
  6. Severe lipid disturbances (triglyceride and/or total cholesterol concentration > 300 mg/dl)
  7. Chronic administration of drugs with confirmed nephrotoxicity and/or sympathicomimetics
  8. Obstructive and restrictive pulmonary diseases which may deteriorate the function of the respiratory system

Relevance to patient case: not relevant