High intraocular pressure is the most well documented glaucoma risk factor; however many patients develop and/or show progression of glaucoma in its absence. It is now thought that in some instances, ocular perfusion pressure (blood pressure – intraocular pressure) may be as important as intraocular pressure alone. Thus, systemic hypertension would be protective against glaucoma. Epidemiological studies, however, are inconclusive. One theory of why hypertension may not protect against elevated intraocular pressure in spite of increasing ocular perfusion pressure is that with time, morphological changes to the vasculature and autoregulatory failure outweigh the benefits of improved perfusion pressure, ultimately leading to poor retinal and optic nerve head blood supply. In this study we showed the presence of increased wall:lumen ratio and wall area of the ophthalmic artery in rats with chronic hypertension in addition to failure of retinal autoregulation in response to acute modification of ocular perfusion pressure. Subsequently we found that in spite of dramatically increasing ocular perfusion pressure, chronic systemic hypertension failed to protect retinal structure and function from a rodent model of glaucoma. In many cases however, glaucoma can develop and/or progress in its absence5. Thus, investigators have sought to understand the role of systemic risk factors in glaucoma. Emerging from these studies is the consistent finding that vascular risk factors can impact upon optic nerve head (ONH) and retinal blood supply and may be critical in glaucoma pathophysiology11. Systemic hypertension may be a critical factor in this vascular hypothesis of glaucoma, however its role is not without controversy12. Ocular perfusion pressure (OPP) is the difference between mean arterial pressure (MAP) in the ophthalmic artery and IOP. As the retina does not store glucose, adequate tissue perfusion is critical to maintaining retinal function, and as the eye is subjected to constantly changing OPP, it relies on vascular autoregulation to buffer this variation15. Experimental and clinical studies suggest that it is not necessarily excessive IOP that leads to glaucoma, rather insufficient OPP, which may arise by virtue of either high IOP or low BP (blood pressure)18. As Khawaja et al.19 highlighted, the relationship between BP, IOP and OPP is complex, and it is somewhat difficult to isolate the contribution of BP or IOP as part of OPP towards glaucoma risk.Glaucoma is the second leading cause of blindness worldwide21. Paradoxically, a number of population based studies also find that systemic hypertension increases glaucoma risk25. The reason for this apparent contradiction may be that whilst low BP promotes hypoperfusion of the retina and optic nerve, chronic periods of hypertension may also promote poor blood supply due to the development of arteriosclerosis and autoregulatory failure. As OPP is not a static entity, adequate autoregulatory capacity, achieved by reflexive alterations in vascular resistance, is necessary to buffer changes in tissue perfusion pressure26.There is strong evidence that low BP increases glaucoma risk22. Additionally, both the Egna-Neumarkt and Los Angeles Latino Eye Studies found both hyper- and hypo-tension were associated with increased risk of glaucoma25. In particular low diastolic perfusion pressure and high systolic perfusion pressure carried an increased risk of glaucoma. These findings lend support to the hypothesis that whilst low OPP is undoubtedly detrimental, changes to the vasculature that occur as a result of long periods of hypertension may eventually undermine the benefit of increased OPP afforded by hypertension.The Baltimore Eye Survey found hypertension was protective against glaucoma in younger subjects and increased glaucoma risk in older subjects27. In animals with the same OPP, retinal susceptibility to injury was altered by the duration of systemic hypertension. Therefore it is not merely the perfusion pressure itself but the perfusion pressure status, encompassing perfusion pressure along with autoregulatory capacity and vascular morphology, which is important in maintaining adequate tissue perfusion. In our experiment, we sought to extend the duration of systemic hypertension further, to 12 weeks, in order to further explore the temporal aspects of the relationship between blood pressure and perfusion pressure status.Experimental studies in rats find that high BP preserves retinal function during acute IOP challenge, however the degree of protection becomes blunted in the presence of a longer duration of hypertension (one hour vs four weeks)29. Cerebral autoregulation is known to be altered in chronic hypertension30. Additionally, a blunted response to a metabolic challenge of retinal autoregulation has been found in humans with chronic hypertension32. Changes to vascular morphology may underlie poor perfusion and autoregulatory deficits. In this study we sought to investigate the effect of chronic hypertension on retinal autoregulation in response to OPP modification. In these rats we also examined the morphology of the ophthalmic vasculature, as the mechanisms hypothesised to underlie a BP mediated altered susceptibility to high IOP. After investigating these effects, we aimed to test whether the benefits of improved OPP in hypertension would be outweighed by the altered perfusion pressure status when chronic systemic hypertension was overlaid with chronic ocular hypertension.In addition to poor perfusion pressure, impaired autoregulation has been linked to glaucoma riskIn the hypertensive group (continuous subcutaneous angiotensin II (ANG II) infusion), systolic blood pressure (SBP) increased steadily over the 12 weeks of infusion from a baseline of 123.0 ± 2.5 mmHg to 161.3 ± 4.6 mmHg at week 12  and plotted as a function of change from baseline MAP (∆MAP). In Fig. 2 compared to 0.57 ± 0.01 mm2 in control animals (p < 0.001). Consistent with the changes observed in the aorta, 12 weeks of hypertension resulted in a 50% increase in ophthalmic artery WLR compared to control animals . Likewise, the ophthalmic artery wall area of treated animals was also increased by 50% . The aorta elastin:wall ratio  and long term BP integral  but not with ophthalmic artery WLR (p = 0.7). In Fig. s = −0.65) when only hypertensive animals are considered.As vasodilation in normotensive animals peaked at ∆MAP −55.0 mmHg Fig. , the % cInterestingly, while we observed a relationship between aortic morphological changes and retinal autoregulation Fig. , we wereP3), bipolar cell (Vmax) or ganglion cell  response amplitudes. The oscillatory potential (OP) peak amplitude was reduced at week 8 and week 12, relative to week 4 in hypertensive animals, but was not used to assay the effect of chronic hypertension on retinal susceptibility to chronic IOP challenge, as there was no IOP related effect. These data are presented in Supplementary Materials Given the above vascular deficits, we sought to ascertain whether the ANG II model of chronic hypertension altered retinal function. There was no significant effect of hypertension on photoreceptoral (RmOHT) (p < 0.001). The fellow eyes (Normotensivecontrol) showed no significant change in IOP throughout. Likewise, in the hypertensive animals, IOP was elevated from a baseline of 14.8 ± 0.4 mmHg to 21.5 ± 1.0 mmHg (week 5–12 average) in OHT eyes , and remained unaltered in control eyes (Hypertensivecontrol). In both groups, an initial spike in IOP was observed immediately post suture , which recovered to below 40 mmHg within three hours. Given that the different BP groups showed a similar IOP profile, HypertensiveOHT eyes are theoretically afforded a higher OPP than NormotensiveOHT eyes  eye as shown in Fig. yes Fig.  based onP3 −14.7 ± 3.5%), bipolar cell (Vmax −12.0 ± 2.8%) and ganglion cell (pSTR −27.5 ± 8.2%) amplitudes. Similarly, IOP elevation in hypertensive animals significantly reduced photoreceptor (−5.4 ± 2.0%), bipolar cell (−6.9 ± 2.8%) and ganglion cell (−32.1 ± 7.4%) amplitudes. To consider whether ganglion cell function was more affected than upstream neurons, comparisons were made within each BP group between ERG parameter and time. There was a significant interaction between ERG parameter and time in both normotensive and hypertensive animals , with post hoc testing revealing that ganglion cell dysfunction was greater than photoreceptoral and bipolar cell deficits at weeks 8 and 12. Whilst chronic hypertension reduced oscillatory potential amplitudes , communicating to bipolar cells (Vmax), which input to ganglion cells . As such, losses in inner retinal function (STR) may reflect damage to retinal ganglion cells and/or reduced input from upstream neurons33. One way to account for this potential confound is to express one ERG component relative to its upstream counterpart34. In this case we examine the difference between the change ganglion cell output (pSTR %) for a given change in its presynaptic partner neuron the bipolar cells (Vmax %). Figure 27. A key difference between this study and previous work was the time course of systemic hypertension, with previous studies employing either an acute increase in BP or four weeks of chronic hypertension, whereas the current study considered 12 weeks of chronic hypertension. Perhaps chronic hypertension will become deleterious to retinal function in the context of chronic IOP challenge with even longer durations of blood pressure elevation.The major neuronal classes in the retina, and thus the ERG signal, are arranged in a serial manner, with the through pathway consisting of photoreceptors  scan around the ONH Fig.  was usedThe circumlimbal suture model did not produce any gross disturbance of retinal structure or axon bundle arrangement at the ONH Fig. . Cell deWhilst a significant reduction in cell density of the ganglion cell layer was observed, with histology, no significant reduction in the GCC thickness was observed with OCT. This may be due to the relatively larger contribution of the inner plexiform layer to the overall GCC thickness masking a change in the relatively small contribution of the ganglion cell layer. Alternatively, it is possible that the OCT segmentation did not completely differentiate between the retinal nerve fibre and ganglion cell layers, and thus the reduction in retinal ganglion cell density contributed to the reduction in RNFL thickness observed with OCT.27. One way to explain this would be that that the protective effect of higher blood pressure against IOP elevation is eroded with increasing chronicity of systemic hypertension. Consistent with this idea, He et al., did find that 4 weeks of chronic hypertension27 was less protective than acute hypertension16. Our findings are also broadly consistent with clinical observation. More specifically, the Baltimore Eye Study found systemic hypertension to be protective against glaucoma in younger patients, but increased the risk of glaucoma in older patients, with presumably more advanced effects of long standing blood pressure elevation including arteriosclerosis22. Both the Egna-Neumarkt and Los Angeles Latino Eye Studies found both hypo- and hyper-tension to be associated with increased glaucoma risk, suggesting that whilst hypotension can promote poor perfusion of the optic nerve head, hypertension, if long standing, could also lead to compromised optic nerve head perfusion, due to arteriosclerosis and autoregulatory failure25.The salient finding of this study was that despite affording a dramatic increase in putative OPP Fig. , chronic32. To our knowledge ours is the first study reporting that chronic hypertension results in impairment of retinal autoregulation driven by systemic blood pressure modification in rats. Impaired pressure induced vasodilation in retinal arterioles might arise from stiffening of the vascular walls as evidence by an increased wall:lumen ratio36, and vascular endothelial dysfunction via oxidative stress leading to a reduction in nitric oxide bioavailability40. Although the literature suggests that impaired vasodilation in hypertension is largely due to endothelial dysfunction and consequent reduction in nitric oxide bioavailability43, as retinal vessels were not examined histologically, structural changes to inner retinal vessel walls could not be ruled out.Another key finding from this study was that chronic systemic hypertension significantly reduced retinal autoregulatory capacity during an acute reduction in OPP. Chronic systemic hypertension has been shown to reduce the retinal vascular response to flickering light, a metabolic driver of autoregulation, in humansThe precise mechanism underlying our finding that chronic hypertension did not protect the retina against chronic IOP elevation is not clear. Here we propose two potential mechanisms. Firstly, our observation of impaired vasodilation during acute OPP lowering Fig.  points tophthalmic – IOP). The equation presumes that peripherally measured BP  faithfully reflects the pressure in the ophthalmic artery and inner retinal vessels. In Fig. ophthalmic in patients  with chronic systemic hypertension. With increasing divergence in vascular remodelling of large and small vessels, the approximation of OPP would become progressively less accurate. OPP as it is currently estimated may need to be modified by to reflective of the severity and chronicity of systemic hypertension. Additionally, OPP estimated in a clinical setting does not capture diurnal variation in OPP and does not consider the capacity of the eye (i.e. autoregulation) to respond to OPP fluctuations. OPP status, which also includes consideration of autoregulatory capacity, could be a more clinically relevant index than the current concept of OPP. The Thessaloniki Eye Study group have used the terms BP and OPP status, to suggest that a normotensive patient and a patient that is normotensive by virtue of anti-hypertensive therapy cannot be regarded in the same way46. The idea is that in the patient receiving anti-hypertensive therapy, a residual impairment of autoregulatory capacity may persist in spite of having recovered to an ostensibly normal BP level. The Thessaloniki Eye Study Group found an association between lower BP and enlarged cup:disc ratio  and between lower OPP and glaucoma risk, only in patients who used antihypertensive medications47. Patients who had lower BP but were normotensive did not show the same associations. Given that anti-hypertensive therapy has the potential to reverse vascular remodelling and endothelial dysfunction49, it is possible that given sufficient time, the detrimental effects of hypertension on the ophthalmic vasculature leading to increased glaucoma risk could be reversed with treatment. Our data would support the concept of OPP status as an index of risk, which would encompass IOP and BP in addition to the severity and chronicity of systemic hypertension and the retinal autoregulatory capacity.Secondly, the putative improvement in OPP may actually be an artefact of the manner in which OPP is calculated . In this study male Long Evans rats were used . Animals were housed in a 20 °C facility with a 12 hour light/dark cycle , with free access to water and rat chow .in vivo retinal vessel imaging, to assess retinal autoregulatory capacity, after 12 weeks of systemic hypertension. Group-2  underwent an IOP elevation surgery on one eye after four weeks, and had retinal function (electroretinography) and in vivo retinal structure  measured at four weekly intervals for the duration of the 12 weeks. At the conclusion of 12 weeks of systemic hypertension, all 34 animals underwent cardiac perfusion prior to tissue collection. Samples of the aorta and ophthalmic artery were obtained from all animals. Retina and optic nerve samples were also obtained from animals in Group-2. The experimental timeline is schematised in Supplementary Material A total of 34 rats were used in this 12 week study . Group-1  underwent acute pharmacological BP manipulation and −1 min−1 of ANG II . Subcutaneous ANG II infusion is a commonly used drug-induced model of systemic hypertension36.Two modalities of BP manipulation and monitoring were used. For chronic BP elevation, all animals were implanted at baseline with an osmotic minipump  under the skin to deliver a continuous infusion of angiotensin II  or normal saline (normotensive controls). The procedure for osmotic minipump implantation is further detailed in Supplementary Material 55. Pilot data from our laboratory in Long Evans rats estimated femoral MAPas 0.91 * tail cuff SBP + 16.3.All animals underwent weekly conscious systolic BP (SBP) measurements using a tail cuff sphygmomanometer . Animals were gently restrained in a custom built restrainer and BP was measured every two minutes over a 30 minute period to derive an average reading. Prior to any BP manipulation surgery, five days of baseline measurements were taken. To minimise the effects of stress in response to restraint, animals were acclimatised to five days of sham BP measurements prior to baseline data collection. SBP was used to estimate mean arterial pressure (MAP), in order to calculate OPP (OPP = MAP – IOP) over the 12 weeks in animals in Group-2. Previous studies have validated the use of tail cuff sphygmomanometry to estimate MAP−1 at a rate of 0.003–0.008 ml min−1 was used to reduce MAP to approximately 50 mmHg. A concentration of 0.065 mg mL−1 ANG II was infused at a rate of 0.004–0.01 ml min−1 to increase MAP to approximately 190 mmHg. The two agents were infused through separate intravenous cannulas. During this procedure, BP was continuously monitored with a cannula in the femoral artery. The surgical procedure for cannulation of the femoral artery and veins is described in Supplementary Material After 12 weeks of chronic hypertension animals in Group-1 underwent acute pharmacological BP manipulation to challenge autoregulation. Intravenous infusion of sodium nitroprusside 0.6 mg mL53. Animals in Group-2 underwent retinal vessel imaging during acute BP manipulation. The procedure for retinal vessel imaging and analysis is described in Supplementary Material Retinal vessel diameter change in response to changes in systemic BP is a commonly used surrogate measure of autoregulatory capacity57. This procedure is detailed in Supplementary Material Animals in Group-2 underwent surgery to chronically elevate IOP after four weeks of systemic hypertension. A circumlimbal suture model of chronic ocular hypertension (OHT), previously described was usedRebound tonometry  was used for monitoring IOP. Five days of baseline measurements were taken prior to the commencement of the study. Thereafter IOP was measured weekly in all animals in Group-2 for the 12 weeks of the study. At the time of the circumlimbal suture surgery, IOP was measured immediately prior to induction of general anaesthesia, after induction of anaesthesia, and at two minutes, 24 hours and 48 hours post tightening of the circumlimbal suture. Excluding the time points zero and two minutes, all IOP measurements were conducted in awake animals without the use of topical anaesthesia.59. The procedures for signal acquisition and analysis are detailed in Supplementary Material P3), bipolar cell (Vmax) and retinal ganglion cell  were assayed in this study. Additionally, oscillatory potential (OP) amplitudes were extracted from the ERG waveform.A dark-adapted full-field electroretinogram (ERG) was used to assay retinal function in animals in Group-2 at baseline and every 4 weeks for the duration of the study. The ERG is a well established technique for non-invasive objective assessment of retinal functionSpectral domain optical coherence tomography (OCT)  was used as a non-invasive assay of retinal thickness. It was performed on animals in Group-2 immediately after each ERG recording. Total retinal thickness, in addition to ganglion cell complex (GCC) and retinal nerve fibre layer (RNFL) thickness was assessed. Acquisition and analysis of OCT signals is described in Supplementary Material Histology was used to assay the effect of hypertension on arterial morphology and the effect of raised IOP on retinal cell density. At the end of the 12 week study period, all animals underwent cardiac perfusion and tissue harvest. Sections of the aorta and ophthalmic artery were obtained from animals in both groups and stained with Gomori’s Aldehyde Fuchsin staining. Cross sections of retinal tissue were obtained from animals in Group-2 only and stained with Haemotoxylin and eosin. Two 500 μm long sections (one from either side of the optic nerve head) were analysed for each eye. The sections were 5 μm in thickness. Tissue collection, preparation and staining procedures are described further in Supplementary Material 60, with Bonferroni post hoc testing was used to assess the effect of chronic hypertension on retinal autoregulatory capacity . To analyse the relationships between parameters a Deming regression was used, along with a non-parametric Spearman correlation coefficient (Prism 6). Two way repeated measures ANOVA with Bonferroni post hoc testing was used to compare the effects of chronic hypertension on retinal function, as well as retinal functional and structural susceptibility to chronic IOP elevation (Prism 6).Group data in this study are presented as the mean ± standard error of the mean (SEM). Data normality (Kolmogorov-Smirnov test) and homogeneity of variances (Bartlett’s test) were established using Prism 6 software . A restricted maximum likelihood (REML) analysisSupplementary material


The aim of the present study was to investigate the association of resting PaO2 with percent time of SpO2 below 90% (T90) and 88% (T88) in 24 hours. We also evaluated the capacity of hypoxia measures to predict PH in patients with idiopathic pulmonary fibrosis (IPF).The quantification of hypoxia based on resting partial pressure of arterial oxygen . Patients were divided into three groups according to resting PaO2: 55-55.9 mmHg (A); 60-60.9 mmHg (B); ≥ 70 mmHg (C). PH was defined as “likely” if SPAP > 50 mmHg, and as possible for SPAP between 37 and 50 mmHg.This cross-sectional study included 27 patients with IPF presenting PaOp ≤ 0.01) and T88 (p = 0.02). PaO2 was inversely correlated with T90  and T88 . Hypoxia variables did not correlate with SPAP, and were not able to predict PH.T90 and T88 in Groups A, B, and C were as follows: 59.9±29% and 44.1±34%; 49.3±34% and 29.9±31%; 17.1±25% and 8.8±18% respectively, with significant differences between the groups for both T90 (2 below 90% and 88% in 24 hours revealed periods of severe hypoxia even in patients with borderline-normal resting PaO2. However, none of the present hypoxia variables was capable of predicting PH.Percent time of SpO PH is aet al. [Traditionally, PH associated with chronic lung diseases has been attributed to alveolar hypoxia. Animal models suggest that chronic alveolar hypoxia causes PH through a combination of sustained vasoconstriction and vascular remodeling. It is generally accepted that vasoconstriction plays a major role during initial stages of the disease, whereas structural remodeling of the pulmonary vascular bed becomes more important during later stages of the disease. This hypothesis is supported by the observation that oxygen administration becomes less effective to reduce pulmonary arterial pressure with increased duration of chronic alveolar hypoxia. The lack of response to oxygen therapy, in turn, suggests that PH results, at least in part, from structural remodeling that is irreversible or only minimally reversible . Neverthet al.  have sho2) often decreases during exercise in patients with IPF. In addition, the severity of intermittent sleep oxygen desaturation has been previously associated with shorter survival in patients with IPF [2) may mask the impact of activities of daily life and sleep.An aspect that has been overlooked regarding the role of hypoxia in the establishment of PH is the method used to measure the degree of hypoxia. Peripheral capillary oxygen saturation  and 88% (T88) in 24 hours (to incorporate the effect of activities of daily living and sleep) in a group of patients with IPF. In addition, we evaluated the ability of different hypoxia measures to predict PH in this sample.The present study aimed at correlating resting PaO22 ≥ 55 mmHg, and not receiving home oxygen therapy. Exclusion criteria were chronic pulmonary thromboembolism and clinical or echocardiographic evidence of left ventricular dysfunction.A cross-sectional study was carried out with 27 patients selected consecutively from the Interstitial Lung Disease Clinic at a tertiary referral hospital . IPF was diagnosed according to American Thoracic Society/European Respiratory Society criteria [The study was approved by the Ethics Committee at Universidade de Brasília. All participants signed an informed consent form.2.1A-aO2 considering a local atmospheric pressure of 680 mmHg, with respiratory quotient of 0.8 for all patients.Forced vital capacity (FVC) was determined following American Thoracic Society guidelines . For blo2: borderline for indication of home oxygen therapy (PaO2 55 to 55.9 mmHg) (Group A); intermediate (PaO2 between 60 and 69.9 mmHg) (Group B); and mild hypoxia or normal PaO2 (PaO2 = 70 mmHg) (Group C).For the present study, patients were divided into 3 groups, according to resting PaO2 below 90% (T90) and 88% (T88) was measured in relation to the total 24-h period.Oxygen saturation was measured over 24 hours using a wrist-worn pulse oximeter  attached to the index finger in the non-dominant hand. Patients were instructed to keep their habitual activities. 24-h measurements were analyzed using the nVision software v. 5.1e . The percentage of wake and sleep time with SpO2.2Transthoracic Doppler echocardiography was performed with patients in the lateral recumbent position using an ultrasound device  with multi-frequency transducer (2.5 to 3.5 MHz). Standard projections were used.Chamber quantification and ventricular function assessment were performed as recommended by the American Society of Echocardiography . Real-tiSPAP was calculated based on tricuspid regurgitation using the modified Bernoulli equation. The pressure gradient between the right ventricle and right atrium was thus obtained. Estimated right atrial pressure was added to the Doppler-determined gradient , considePH was defined as “likely” if SPAP > 50 mmHg , 14. PH 2.32, DA-aO2, SPAP) had normal distribution, group means were compared using one-way analysis of variance (ANOVA). Correlations were evaluated using Pearson’s coefficient. For the binary yes/no variables  logistic models were employed for each indicator of hypoxia , and odds ratios were calculated for these predictors with 95% confidence intervals. Means are presented with standard deviations. Significance was defined as p < 0.05. SPSS v. 20 for Mac was used for the analyses.The distribution of continuous variables was determined using the Kolmogorov-Smirnov test as well as a Q-Q plot, a graphical representation in which normal distribution is represented by a straight diagonal line. Since all variables under study  and 12 females (44.4%) and comprised different stages of the disease. Mean age was 71.4±11 years, ranging from 43 to 88 years. Mean FVC was 2.23±0.74 L, ranging from 1.08 L to 3.63 L. Mean % of predicted FVC was 72.6±22%, from 45% to 93%.1 shows the odds ratios (OR) for each predictor variable analyzed .The logistic regression models employed in this study were not capable of predicting PH, either likely or combined analysis of possible + likely PH. Table 2, and DA-aO2 with SPAP. SPAP could not be estimated in one patient in whom tricuspid regurgitation was absent, and thus 26 patients were included in this analysis. Pearson’s coefficients for the correlation between SPAP and hypoxia variables were as follows: -0.197 (p = 0.33) for PaO2; 0.099 (p = 0.62) for DA-aO2; 0.191 (p = 0.35) for T90; and 0.157 (p = 0.44) for T88.Along the same lines, only a weak and non-significant correlation was observed for T90, T88, PaO2 measurements. Table 2 shows T90 and T88 values according to hypoxia severity. Fig. (1A and B) emphasize these individual values in a scatterplot. It should be noted that even in patients with borderline normal PaO2, SpO2 below 90% was detected during a period corresponding to 17% of the day, that is, more than 4 h. This hypoxia duration was higher in groups with lower PaO2, with statistically significant differences. Indeed, resting PaO2 had a negative and moderate correlation with T90 , but not with T88 . None of the patients presented T90 or T88 of zero, although six patients of the 15 classified in group C (PaO2 = 70 mmHg) had T90 < 2%.Despite the inability of hypoxia data to predict PH and the lack of correlation with SPAP values, the results show that 24-h hypoxia levels were higher than expected considering resting PaOp = 0.08). Mean T88 was 18.2% and 22.6% during wake and sleep periods respectively (p = 0.18). Hemoglobin saturation declined at a slightly higher hourly rate during the wake period, 11.6 vs. 10.9 during sleep (p = 0.63).The analysis of sleep and wake periods revealed higher T90 and T88 during sleep, however without statistical significance. In six patients, we were unable to adequately discriminate between sleep and wake periods, and thus 21 patients were included in this analysis. Mean T90 was 30.7% and 37.1% during wake and sleep periods respectively  was slightly higher during sleep, even though the comparison was not statistically significant. This was probably due to the hypoventilation that occurs during sleep even in normal individuals . No sign2. However, based on the present results, these variables are not useful to predict PH in IPF. The same was true for PaO2 and DA-aO2.T90 and T88 measures in 24 hours reflect hypoxia in patients with borderline-normal PaO


Whilst hematospermia may indicate urological disease, it is a rare manifestation of severe systemic hypertension. We describe the case of a young man with hematospermia associated with a blood pressure of 228/135. Blood pressure treatment led to resolution of his hematospermia. Physicians must be aware of this potential association. Hematospermia may occur as a presenting symptom to primary care doctors, emergency doctors, and urologists. It is an alarming symptom for patients, yet may be under‐reported due to patient embarrassment. In young patients, it is almost never a sign of urological malignancy, and usually points toward a self‐limiting disease, such as prostatitis, urethritis, or epididymo‐orchitis A review of guidelines in the medical literature reveals a focus on urological investigations, such as prostate imaging and biopsy A 28‐year‐old Caucasian man living in London presented at a walk‐in GP clinic reporting four episodes of hematospermia over 10 days. In the first three episodes, the patient reported the semen being brown in color. On the fourth episode, there were distinct streaks of red blood within the semen.The man was heterosexual, and this was his first and only sexual partner. His partner had no history of sexually transmitted infections (STI). The couple was sexually active and using barrier method contraception for family planning reasons.The patient was otherwise fit and well with no past medical history apart from mild childhood asthma. He had no headaches or changes in vision. He had no cardiac or respiratory symptoms. There was no history of recent trauma. There were no changes in urinary or bowel habits. He had no pain, fever, sweats, weight loss, or fatigue. He had not travelled abroad recently. The patient had never smoked or taken illicit substances. His diet was reasonably healthy, and he walked approximately 5 km a day. He consumed approximately 32 units of alcohol per week and recognized that this as in excess of medical guidelines. There was no family history of inheritable diseases.On examination, he was comfortable at rest and clinically euvolemic. His abdomen was soft and nontender. His kidneys were not palpable. There were no renal bruits. There was no enlargement or masses in the scrotum. A digital rectal examination was normal with no enlargement or nodularity of the prostate. Respiratory examination revealed normal breath sounds. Examination of the central and peripheral nervous system was entirely normal.On cardiovascular examination, heart sounds were normal. There was no peripheral edema, and the jugular venous pressure was not raised. There was no radio‐femoral delay, and fundoscopy was normal. His blood pressure was note to be 228/135 mmHg, and his heart rate was 90 beats per minute and regular. Pulse volume and character were normal. His oxygen saturations were 98% on room air. There were no signs of acromegaly or Cushing's syndrome.Urinalysis was completely negative. His electrocardiogram (ECG) showed normal sinus rhythm. There was no left ventricular hypertrophy, axis deviation, or strain pattern.9/L, white blood count 5.9 × 109/L, and mean corpuscular volume was 85 fl. His CRP was <1 mg/L. His urea and electrolytes were sodium 142 mmol/L, potassium 4.3 mmol/L, urea 4.7 mmol/L, and creatinine 96 mmol/L. His estimated glomerular filtration rate was slightly reduced at 84 mL/min. His chest radiograph was normal. Ultrasound and computerized tomography of the urinary tract were normal.His full blood count was as follows: hemoglobin 174 g/L, platelets 234 × 10Twenty four‐hour urinary metanephrines and a serum renin–aldosterone level were with normal range, ruling out pheochromocytoma and hyperaldosteronism as causes of hypertension, respectively. An echocardiogram was entirely normal. More specifically, there was no left ventricular hypertension nor diastolic dysfunction, which would be the expected findings in a case of chronic hypertensive heart disease.A diagnosis of hematospermia secondary to severe essential hypertension was made. There were no clinical signs of malignant hypertension. The absence of other urological symptoms made inflammation or infection of the urinary tract unlikely, and the lack of proteinuria or left ventricular hypertrophy on ECG implied that the hypertension was of recent rather than chronic onset.The patient was treated with an angiotensin‐converting enzyme inhibitor (ACE‐i), per National Institute for Health and Care Excellence guidelines. A dosage of 2.5 mg of ramipril daily was sufficient to control his blood pressure.The patient purchased a home blood pressure machine and monitors his blood pressure daily. His systolic pressure lowered steadily to an average of 165 mmHg. Normotension led to complete resolution of the hematospermia.Hematospermia is almost always a benign and transient phenomenon Hematospermia is only rarely associated with prostatic malignancy. Cohort studies have described an incidence of 0.5% in cases of prostate cancer Severe hypertension is a recognized but rare cause of hematospermia Severe essential hypertension in young patients is uncommon. It is crucial to diagnose it early, as prolonged hypertension places an otherwise healthy patient at risk of end‐organ damage. Hypertensive urgency – or malignant hypertension – is a dangerous condition that may lead to irreversible damage to the central nervous system, retinas, or the kidney, but many cases are asymptomatic. It is therefore feasible that a young man could present to a physician with hematospermia and no other signs or symptoms of disease, and not have his BP measured as part of the assessment. This case is therefore an important lesson in the initial clinical workup of this symptom; the hematospermia is a benign and temporary occurrence, but the underlying blood pressure abnormality is potentially serious and requires urgent management.Hematospermia in young males without other red flag symptoms is almost exclusive benign and self‐limiting. Whilst uncontrolled hypertension in this cohort is uncommon, consideration of severe hypertension as a cause of hematospermia must be considered by the treating physician, as correction of the abnormal blood pressure will be the priority consideration.None declared.MA: wrote the main body of the case report. CH: reviewed the manuscript and made material changes and revisions. BL: critically appraised the manuscript content and made minor revisions.


Case-control observational study to evaluate the microvascular and macrovascular changes in patients with hypertension secondary to primary aldosteronism (PA), essential hypertension (EH) and healthy subjects. Measurements of arterial stiffness including augmentation index (AIx) and pulse wave velocity (PWV) were assessed using a TensioClinic arteriograph system. Retinal microcirculation was imaged by a Retinal Vessel Analyzer (RVA) and a non-midriatic camera (Topcon-TRC-NV2000). IMEDOS software analyzed the retinal artery diameter (RAD), retinal vein diameters (RVD) and arteriole-to-venule ratio (AVR) of the vessels coming off the optic disc. Thirty, 39 and 35 patients were included in the PA, EH and control group, respectively. The PA group showed higher PWV values compared only with the control group. The mean brachial and aortic AIx values did not show significant difference between groups. In the PA group, the mean RVD and AVR values were significantly lower than in the EH and control groups, whereas the parameters did not differ between the EH and control groups. In conclusion, AVR appears significantly modified in the PA group compared with the EH group and could represent an early and more reliable indicator of microvascular remodeling. PA has been associated with a higher incidence of cardiovascular events than essential hypertension (EH), due to aldosterone pressure-independent effects, with marked target organ damage affecting the heart, carotid artery and kidneys2.Primary aldosteronism (PA) is a common cause of arterial hypertension and represents the most frequent form of secondary hypertension4. These changes in extracellular matrix are able to modify profoundly the microvascular structure and play an important role in the development of cardiovascular fibrosis and the consequent increase in the rigidity of such structures. The etiopathogenetic mechanism by which aldosterone is able to effect such changes has not yet been completely identified, although it is known that aldosterone helps substantially in the accumulation of different collagen fibers and growth factors in vascular walls in patients with PA5.Recent studies of patients affected by PA have demonstrated an increased accumulation of collagen, especially type III, even in small arteries and arterioles, compared with normotensive and essential hypertensive subjectsin vivo evaluation of these changes involves an invasive approach through biopsy4. For this reason, there is currently considerable interest in research on the development of non-invasive methods used in the study of vascular remodeling and arterial stiffness alterations. Arterial stiffness seems to be a predictor of future cardiovascular events in hypertensive patients and is especially high in PA compared with EH9.To date, the only possible in vivo study of the structure of small arterioles and venules and of their modifications in relation to systemic disease processes such as hypertension and diabetes.The retina represents a unique site where the microvasculature can be directly and non-invasively visualized. Retinal microvasculature assessment offers an opportunity for detailed 10, no information is available regarding the retinal microvascular changes associated with PA and their correlation with the macrovascular compartment.Despite the increasing use of retinal vascular imaging in evaluating the alterations of retinal microvascularization in patients with EH and the demonstrated homology between retinal microvascular morphology and peripheral small resistant arteriesOn the basis of the different pathogenetic mechanisms of arterial hypertension secondary to PA and in the EH, the current pilot study aimed to provide a preliminary analysis of the modifications in microvascular retinal circulation and in the macrovascular compartment in patients with arterial hypertension related to PA and EH.Demographic characteristics of patients with PA, EH and the subjects in the control group are shown in Table There were no significant differences in age, gender and smoking habits between the groups; the body mass index was significantly lower in the control group, whereas it appeared similar in patients with PA and EH. Systolic and Diastolic blood pressure (BP), both measured in the clinic and during 24-hour ambulatory blood pressure monitoring (ABPM), were comparable in patients with PA and EH and were found to be statistically different from the patients in the control group. Mean known duration of hypertension was also similar between the PA and EH groups. No significant difference was found in the proportion of the different classes of anti-hypertensive drugs or in statin use. As expected, the plasma aldosterone concentration was significantly higher and plasma renin activity levels significantly lower in patients with PA as against patients with EH.Pulse wave velocity (PWV), brachial and aortic augmentation index (Aix) data of PA and EH patients and of the control group are listed in Table The mean value of retinal artery diameter (RAD) was found to be lower in the PA group in comparison with the EH and control groups, although each comparison between the three groups did not reveal any significant difference. The lower retinal vein diameters (RVD) in the PA group compared with the EH and control groups was statistically significant. Similarly, a statistically significant reduction in the mean AVR value was found in the PA group in comparison with the EH group and normal subjects. The RVD and arteriole-to-venule ratios (AVR) did not differ between the EH and control groups.The differences in the RAD, RVD and AVR were further analyzed in order to detect the possible influence of age, systolic blood pressure, estimated glomerular filtration rate and pulse pressure Table . In part13.Retinal vascular imaging of the microcirculatory system has attracted considerable attention in the field of cardiovascular research. This is mainly due to the unique possibility of a direct and non-invasive observation of a micro-circulatory system which has high structural and functional homologies with other models, including the myocardial and cerebral systems17.Recent studies have provided new insights into the role of some new parameters, including retinal vascular tortuosity, fractal dimension and bifurcation. Additional investigations also considered the AVR and its role as a risk factor for vascular complications secondary to essential hypertension20. This condition represents the most common endocrine form of secondary hypertension, amounting to 5–15%23 of all cases. It is of special interest that an increased level of aldosterone induces marked changes in the extracellular matrix due to collagen deposit, leading ultimately to an increase in arterial stiffness of the macrocirculation5.Notable vascular remodeling phenomena are also present in arterial hypertension secondary to primary aldosteronismThe aim of the current study was to evaluate the modifications of the microvascular retinal circulation in association with the alterations of macrocirculation in patients with arterial hypertension secondary to PA and EH, compared with a normotensive control group.Our study pointed out that the average values of the AVR were statistically lower in subjects with PA than in patients with EH and in the control group, even after evaluation of age, systolic blood pressure, estimated glomerular filtration rate and pulse pressure as confounding factors. In addition, the AVR did not reveal a statistically significant difference between the group of patients with EH and the control group. At the same time, arterial stiffness analysis revealed a statistically significant increased value of PWV in the PA group, in comparison with the normotensive group, but not versus the group of patients with EH.24. A considerable drawback of the parameter is the loss of the contribution of the single variable. For example, a reduction in the AVR may be the consequence of a reduction in the arteriolar diameter or an increase in the retinal venular caliber or both. In our cohort of patients, the lowest arteriolar diameter values were found in the PA group, compared with the EH and normotensive groups, while the PA group also showed the lowest venule diameter values.AVR consists of a ratio of the caliber of arterioles to venules. In the imaging analysis, it is not affected by magnification differences caused by camera lens adjustments and refractive errors29. In addition, there is increasing evidence that retinal venular widening is strongly related to concurrent elevated BP levels, suggesting a dynamic component responsive to changes in the microcirculation30. Thus, changes in the retinal microvasculature structure observed in the current study seem only partially to corroborate the clinical evidence that abnormalities in the vascular network may be more pronounced in patients with PA.The narrowing of the retinal artery and widening of the retinal venular caliber are both involved in arterial hypertension. The mechanism linking the narrowing of the retinal artery and the development of hypertension is not well understood. However, several studies have demonstrated that increased peripheral vascular resistance is associated with an increased incidence of hypertension and a rise in blood pressure over timeOur data show that PA patients had a greater retinal artery narrowing than EH and healthy subjects, although they did not achieve statistical significance. It is worth noting that a wider retinal venular caliber was not observed in the PA group in our investigation and that although a difference was measured in the RVD between the PA group and the EH and control groups, the difference was no longer significant after correction for the co-variables.32.It should be borne in mind that our sample consisted of patients with recent onset of hypertension and that the changes in the retinal arterial and venular diameters may occur in a long-standing disease and might only appear as a time-related modification. In addition, smoking habits, obesity, statin use or the different classes of anti-hypertensive drugs are all variables able to influence the retinal vascular caliber. Although no difference was registered for all these parameters among the three groups, a different influence might be identified in a larger population study. Finally, we should consider the wide variability in the retinal venous caliber in patients with arterial hypertension, as demonstrated in the Rotterdam and MESA studies, where an increased venous diameter and a reduced venous diameter were found also to be associated with arterial hypertension33 and that patients with PA show a higher incidence of stroke in comparison with matched EH patients34.Previous investigations provide evidence that some retinal microvascular abnormalities are strictly related to target end-organ damage. In particular, it has been reported that a wider retinal venular caliber is related to a risk of stroke rather than a narrower arteriolar caliberOnly longitudinal studies, with a larger cohort of patients, a long-term follow-up and targeted histological studies, will be able to provide additional material to test the hypothesis linking the changing of the retinal venular caliber and the prevalence of stroke in patients affected by PA.35, the absence of a meaningful difference in the PWV and the AIx parameters between PA patients and the HE group in our investigation is not so unexpected. Tsioufis et al. registered higher mean PWV values in patients with early diagnosis of hypertension secondary to PA than in HE patients18. However, the study failed to reach statistical significance and a shorter known-duration of hypertensive disease was suggested as the determining factor. As in our study, it is important to bear in mind the small sample used for the study and/or the early stage of the disease when interpreting the data.Analysis of arterial stiffness in the present study demonstrated that patients with PA had higher PWV values than patients with EH and normotensive patients, achieving a statistically significant difference only in comparison with the latter group, whereas no difference in the AIx values was found in each comparison. Although in previous studies patients with PA often displayed an increase in PWV and AIx in comparison with EH patients36. AIx is a complex index describing mainly wave reflections occurring at the branching of the arterioles and appears to be influenced by several confounding factors, including age, height, heart rate, gender, calcium levels, diastolic blood pressure and systolic blood pressure44.The early artery remodeling noted in the present study’s PA group, compared with the control group, may be ascribed to the direct effect of high aldosterone on vascular smooth muscle cells, leading to functional impairment of arterial conduit function. Similarly, previous studies often failed to find differences in AIx values between PA, EH and the normotensive group50. Our population study consisted of patients with PA and EH who were well matched for all these baseline parameters. The reason for the absence of a relevant difference in PWV between PA and EH groups remains to be determined. We hypothesize that the sample size and disease duration could themselves have influenced our results.Several variables may influence PWV, including aldosterone plasma level, weight, age, use of anti-hypertensive drugs or statinsTaken together, our data suggest that retinal microvascular changes and macrovascular modifications secondary to PA appear to manifest differently in comparison with EH. In particular, AVR reduction appeared earlier in PA than in EH and in the normotensive group, while PWV was not yet found to be significantly modified. A peripheral morphological change might be a more reliable indicator of vascular remodeling than the assessment of macrovascular change measured by means of PWV and AIx parameters.52. It is worth noting that AVR appears to be an independent risk factor for stroke. AVR may have a further useful application in relation to the observation that the AVR parameter may increase in response to antihypertensive treatment by modifying the retinal arteriole diameter, expressing an improvement in retinal microcirculation53. In this context, AVR may be a useful indicator as a therapeutic target capable of reflecting the effectiveness of antihypertensive drug treatment in controlling high BP values, PA included.AVR is currently under investigation owing to its association with an increased risk of target organ damage, especially left ventricular hypertrophy56.Moreover, data acquired in the current study will serve as the basis for a future study exploring the dynamic proprieties of the retinal microcirculation by means of a dynamic retinal vessel analyzer. There is growing evidence suggesting that, independently of its effects on blood pressure, aldosterone impairs vascular function through the suppression of nitric oxide formation and that this impairment in endothelium-dependent vascular reactivity is partially reversible through chronic mineralocorticoid receptor blockade. The dynamic retinal vessel analyser offers an accurate and non-invasive method of measuring vessel motility, assessed in terms of retinal vessel response to flickering light stimulation, and can be performed on the main vessels of the posterior pole. Flickering light stimulation of the retina is an original technique that has been used in healthy subjects to investigate the process of neurovascular coupling. Such a mechanism enables the retina to regulate blood flow in response to neural activity. The increase in neural activity induced by flicker stimulation leads to retinal arterial and venous dilation by releasing vaso-active factors, such as nitric oxide, from neural and endothelial cells. In the light of these considerations, the reactivity of the retinal microcirculation may be taken as a model to evaluate the efficacy of specific anti-hypertensive drugsOne of the present study’s strengths lies in its being based on homogeneous groups whose demographic and clinical characteristics appear well matched.However, as mentioned above, the sample size examined in the current study could be considered a limiting factor. Indeed, bearing in mind that retinal vessel caliber varies widely and that hypertension secondary to PA amounts to about 10% of the secondary forms of arterial hypertension, it is essential to perform a study with adequate power and a larger cohort of patients to confirm the outcomes of our pilot study.57. Despite significant improvement in imaging technology, there are still confounding factors in imaging acquisition and interpretation, including refractive error and axial length, which may be partially compensated by AVR assessment.An advantage of computer assisted analysis of retinal microvascular modification is the high inter-observer and intra-observer reliability provided by a trained raterOne additional limitation of this cross-sectional study is the relatively short known-duration of the patients’ hypertension. The changes in arterial stiffness and retinal microcirculation described in this analysis may be distinctive features of a population of subjects with the same characteristics, although these changes evolve at different stages of the disease.Finally, we considered the assessment of a single point of the retinal temporal artery and of the retinal temporal vein as representative of the modifications in the retinal circulation. More generalized indexes, such as the central retinal arterial equivalent and venular equivalent, might be more suitable indicators of peripheral microvascular abnormalities.To our knowledge, this is the first investigation describing the assessment of the retinal microvasculature system in combination with the macrovascular compartment in patients affected by PA. Our data demonstrate that the AVR is greatly modified in PA in comparison with EH and could represent an early and more reliable indicator of vascular remodeling. Although arterial stiffness alteration is more usually associated with PA than with EH, in our study it appeared only slightly affected, displaying an unremarkable increase in the mean PWV value.Longitudinal studies with a large population are required to confirm our preliminary data and to verify the behavior of AVR in response to treatment, including adrenalectomy or medical treatment.We performed a case-control observational study on consecutive adult patients affected by systemic arterial hypertension referred to the Specialized Center of Secondary Hypertension of the Department of Internal Medicine and Medical Specialities  since December 2012. Each consecutive patient with PA and EH and no intercurrent state of illness was offered the chance to be included in the current observational study, highlighting the investigative nature of the study and the absence of any risk in the data acquisition procedures.The study protocol adhered to the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of the G.B. Bietti Foundation and each patient gave signed informed consent before enrolment.58 and including raised biochemical markers of hyperaldosteronism; (b) EH diagnosed by clinic and ambulatory blood pressure monitoring (ABPM) in accordance with the criteria of the guidelines of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC)59; (c) the control group was represented by a population of healthy subjects matched for age and gender, not taking any medicines and with no significant medical history (matching was done by groups of subjects). Normal subjects were recruited on a voluntary basis and were mainly hospital workers or were part of the administrative or medical staff.Inclusion criteria were defined as follows: (a) diagnosis of PA, based on criteria of the Endocrine Society Clinical Practice GuidelineMajor exclusion criteria were defined as follows: secondary prevention for cardiovascular diseases, heart failure, liver cirrhosis, diabetes, kidney failure (Glomerular Filtration Rate (GFR) MDRD < 60 ml/min), cardiac arrhythmias, severe obesity (Body Mass Index (BMI) > 35 kg/m2), peripheral artery disease (PAD). Additional exclusion criteria comprised a history of any ocular condition able to confound an appropriate fundus ocular assessment and especially a history of glaucoma, presence of cataract or media opacities preventing a proper assessment of the retina and the acquisition of the image of the fundus, pathologic myopia and any other type of retinal disorder.60. This technique is based on the fact that the contraction of the myocardium generates pulse waves in the aorta. The pulse wave goes to the arm (first wave), where the cuff is located, then to the aorta. Part of the wave is reflected at the bifurcation of the aorta, goes back, adds to the first and is sensed by the cuff. The first wave is reflected at the bifurcation of the aortic wall; a second, reflected wave therefore appears as a late systolic peak. The morphology of this second wave depends on the stiffness of the large artery, the reflection time at 35 mmHg suprasystolic pressure of the brachial artery (RT S 35) and the peripheral resistance-dependent amplitude.Arterial stiffness was assessed by examining the AIx and the PWV. Measurements were carried out by using a TensioClinic arteriograph system . Details of this device have been previously describedThe cuff collects a pulse wave that contains both the first and reflected waves. The software calculates PWV and AIx from this combined wave. AIx is calculated from the amplitudes of the first and second wave and represents the pressure difference between the pressure of the late systolic peak and that of the early systolic peak divided by the pulse pressure. PWV is the quotient of the jugular fossa–symphysis distance and RT S35 in meters per second. The jugular fossa–symphysis distance is anatomically identical to the distance between the aortic trunk and the bifurcation. All the measurements were performed by a single fully-trained operator in a quiet room and after the participant had rested 10 minutes in a supine position.Each patient received a comprehensive ophthalmological assessment, involving a visual acuity and slit-lamp examination, Goldmann applanation tonometry and ocular fundus evaluation. All patients were imaged by a Retinal Vessel Analyzer (RVA) by positioning the subject in front of a non-midriatic camera (Topcon TRC-NV2000) to obtain a retinographic image (45°). The images were then processed by IMEDOS software measuring the caliber of vessels emerging from the optic disc. The RVA produces continuous and automated analysis of the vessels combined with correction for small eye movements. Using an adaptive algorithm to calculate the size of the vessels (VesselMap 2-Z), this system combines high reproducibility with high temporal and spatial resolution.62. The choice was based on the results of a previous study demonstrating the high correlation in vascular morphology between the left and the right eye63.Measurements of RAD, RVD and AVR were taken between 1 and 2 disc diameters from the margin of the optic disc. The major superior temporal arteries and vein of the right eye were studied  and laboratory testing ).The Shapiro Wilk Test was used to check the assumption of normality of the variables. The Anova statistical test was used for the comparison of continuous variables in the three groups applying the Student-Newman-Keuls correction, while the χ² test was used for categorical variables. The adjustments for the co-variables  were performed applying the Ancova statistical test with Bonferroni correction; each variable was separately analyzed and not included in a model and each comparison was individually adjusted for each co-variable. All statistical comparisons were performed using 2-tailed significance tests, with p < 0.05 considered statistically significant. MedCalc Statistical Software  was used for all analyses.


In ninestudies, capnography values were correlated with carbon dioxide (COmost studies have found a good correlation between capnography values and bloodbiomarkers, suggesting the usefulness of this parameter to detect patients at riskof severe metabolic change, in a fast, economical and accurate way. In the emergency services, to diagnose and evaluate the treatments administered topatients with pathologies as diverse as metabolic or electrolytic changes, hypoxemia andhypercapnia, an arterial blood gas (ABG) test or a venous blood gas (VBG) test isrequired to assess the oxygenation, ventilation and metabolic status,---The assessment of blood acid-base balance is performed using aggressive techniques,which require material resources, team time and are not free of potentialcomplications2 values at the end of expiration  and other variables involved in thebinomial blood acid-base-,,-,-2 measurements in spontaneous breathing patients.Several revised articles suggest the usefulness of capnography for this purpose, given agood correlation between CO,-The types of capnography infrared sensors used in the current monitors are mainlydivided into two types according to their location: mainstream, whose sensor is locatednear the airway ; sidestr,-Some of the revised studiesThe objective of this review is to evaluate the usefulness of capnography for thedetection of metabolic changes in spontaneous breathing patients, in the emergency andintensive care settings.An in-depth and structured bibliographical research was carried out from December 2015to January 2016, in two phases.capnography and metabolicdiseases were selected as root or primary descriptors,acidosis and alkalosis as secondary, and theircombination with the Boolean operators was set as follows: (capnography[MeSH]) AND.Firstly, from the question and objectives of the study, it was obtained the keywordsthat were translated into documentary language or descriptors on Health SciencesDescriptors (DeCS). The entries Considering the areas of knowledge, the following databases were selected for thecollection of primary sources: EBSCOhost [which included the databases: MEDLINEComplete, Cumulative Index for Nursing and Allied Health Literature (CINAHL) Complete,Database of Abstracts of Reviews of Effects (DARE), Cochrane Central Register ofControlled Trials (CENTRAL), Cochrane Methodology Register (CMR), NHS EconomicEvaluation Database (EED), Health Technology Assessments (HTA), Library InformationScience & Technology Abstracts (LISTA), Virtual Health Library (VHL), PubMed,Spanish Medical Index (IME), Spanish Bibliographic Index of Health Sciences (IBECS),Latin American Literature in Health Sciences (LILACS) and Cochrane Library. Theselection of articles was limited to all types of publication in English and Spanishover the last 10 years. Those references whose title and content did not meet theinclusion and exclusion criteria were excluded.2 values; that the objective of the study was to assess thecorrelation between arterial CO2 partial pressure (PaCO2) andEtCO2, only in chronic respiratory patients. In addition, these studiesassessed the use of capnography only in patients submitted to invasive mechanicalventilation and only focused on transcutaneous capnography.  The inclusion criteria were that the article included capnography in the assessment ofpatients with potential metabolic changes, in its title or abstract; that the articleassessed the consistency between the values obtained by capnography and the otherparameters included in the blood acid-base balance; and that spontaneous breathingpatients were included in the study. The exclusion criteria were that the study did notassess the correlation between the gasometric values of blood acid-base balance and theEtCOIn the second phase, a specific research was carried out in order to complete theselection of articles. For this purpuse, some of the citations that the authors of theselected studies used and were relevant for the present study were located andincorporated, as shown in The structured search was performed in pairs as well as the final decision to include orexclude a certain study. In preparing of this article, a worksheet was used for theelaboration of a structured summary about each consulted article . In this worksheet, the degree of adequacy of each article wasassessed using a 4-point Likert scale, according to the criteria and methodologicalquality of the results presented. The Likert scale scoring was as follows: 1 point ifthe article was not relevant for the study objectives, 2 points if it was relevant forthe justification of theoretical framework of the study, but with poor methodologicalquality, 3 points if it was relevant for the study methodology, but with uninterestingresults for the study, 4 points if it was relevant for the methodology, results,conclusions and theoretical framework.After completing the two phases of the bibliographical search, the same strategy wasrepeated by an expert in Documentation Science, using the descriptors and their Booleancombinations over the ten years and the language used in the databases, and the sameresults were found. Thus, the validity of this review was ensured.In the initial phase of this study, 22 articles were selected and 11 critical readingsresulted after applying the inclusion and exclusion criteria. These 11 articles werescored according to the Likert scale . ,In the second phase of the guided search or snowball sampling, another nine articleswere selected, which are presented in Of the 19 articles finally selected, 17 were from the primary search (89.4%) and twofrom the secondary search (10.53%). Regarding the distribution according to the studydesign, 15 were prospective observational studies (88.23%) and two were retrospectiveobservational studies (11.76%), of which five were focused on pediatric patients(29.41%) and the remaining 12 ones were focused on adults (70.59%), as described inThe pathologies studied in the pediatric population were: 3 articles on the use ofcapnography in diabetic ketoacidosis (DKA) and 2 in acute gastroenteritis (AGE). In theadult population, 3 articles were focused on patients cared for in emergency settingsdue to metabolic changes, 4 on dyspneic patients, 2 on septic/febrile patients, 1 on DKAand finally, 2 assessed the Mainstream and Sidestream systems. The sample sizes of thestudies were very variable, ranging from 25 subjects, which was the smallest number ofpatients includedAs for the studies from the secondary search, in one of them2, it was found fourstudies that used simple nasal cannulas (Nc); five used nasal cannulas with oral portion(Nco) for the detection of the air exhaled through the mouth; two used adapters of OTT,through which patients with ventilation breathed; three studies did not specify the typeof cannula used and; three studies used different cannulae or adapters, according to thetype of capnograph used-,Regarding the materials used for parameterization of EtCO-,As for the capnographs used according to their technology, 12 used Sidestreamcapnographs, out of these, seven were of the Microstream type. Only one studyexclusively used the Mainstream2 values after 3-5ventilations.The list of capnographs used is shown in 2 values and the values of thevariables involved in blood acid-base balance, six of the studies compared these valuesusing venous samples, the remaining 11 studies used arterial blood samples. Nine studiesused the Pearson correlation coefficient to analyze the association withPCO2, eight with HCO3, three with lactate, four with blood pH, onewith the Sequential Organ Failure Assessment (SOFA). In addition tolinear correlation, six studies also analyzed the concordance between the measurementsand the results by means of the Bland-Altman Formula (FBA). Regarding the correlation between the EtCO2 > 30mmHg had DKA , correlation between EtCO2 and HCO3¯ (r=0.72). In this study, these findings can be compared with those ofanother study2> 34mmHg is out of range in relation tovalues of HCO3¯ ≤15mmHg (100% sensitivity), whereas EtCO2 ≤ 31mmHgshowed 96% specificity in detecting acidosis in pediatric patients with AGE; indicatinga significant correlation between EtCO2 and HCO3 . Among the pediatric studies, one of them2 and HCO3¯ , and after treatment initiation . Another study2 and pH  and between EtCO2 and PCO2 during continuous monitoring of patients with DKA and, by means of FBA, the limits ofagreement between EtCO2 and PCO2 were defined as 0.8 ± 4.2 mmHg.In a later study2 and PCO2 , and betweenEtCO2 and HCO3¯ . They also assessed the concordance betweenEtCO2 and HCO3¯ by using FBA and the result was -0.51 ± 2.31 mmHg, and betweenEtCO2 and PCO2 was -0.29 ± 4.18 mmHg. In their studiesIn studies targeting adults grouped according to the reason of the consultation, thefollowing results were found.2 and PaCO2, with amean deviation between the two parameters of 12mmHg. The correlation between theEtCO2-PaCO2 gradient and the respiratory rate, obtained by FBA,was weak ; however, the authors did not analyze the directcorrelation between EtCO2 and PaCO2. On the other hand, in anotherstudy2 and PaCO2, butthe concordance between the two values, by means of FBA, was weak, ranging from -10 mmHgto +26 mmHg. It should be emphasized the results of another previous study2 andPaCO2 (r=0.792). Similarly, another study2 and PaCO2 and also a good concordance, by means of FBA, 0.5 ± 5 mmHg . In patients with dyspnea, one study2 and PaCO2 , by FBA, from -0.6 mmHg to25.5 mmHg. With the use of the Microstream system, the correlation betweenEtCO2 and PaCO2 was r=0.41 (p<0.001), by FBA, ranging from-5.4 mmHg to 24.7 mmHg. In another study2 and PaCO2: Non-obese: Mainstream-Nco , Microstream-Nco , Microstream-Nc .Obese patients without OSAS: Mainstream-Nco , Microsteam-Nco , Microstream-Nc . Obese patients with OSAS:Mainstream-Nco , Microstream-Nco ,Microstream-Nc . Among those studies comparing different capnography systems, it was observed astudy2 and PaCO2 and a strong correlation between EtCO2 andHCO3¯ , indicating that values of EtCO2> 24.5mmHg were out of the interval for DKA, with sensitivity of 0.90 and specificityof 0.90. On the other hand, in another study2 and HCO3(r=0.506), it was obtained values of EtCO2 ≤ 25, with a specificity of 84%for acidosis in its sample, and EtCO2 ≥37mmHg, with 100% sensitivity forabsence of metabolic acidosis. Still, in another previous study2 and SOFA  and between EtCO2 and lactate  infebrile and potentially septic patients. However, in a later study2 and lactate,according to the septic status: in patients with sepsis , severesepsis , and septic shock . They studiedthe relationship between EtCO2 values and mortality, obtaining in those whodied, a mean EtCO2 value of 26mmHg ; and for those whosurvived, a mean EtCO2 value of 33mmHg . In another study ofthe same authors mentioned above2 and HCO3¯ , as wellas between EtCO2 and lactate , which was only detectedin 89 patients (n=201). In this case, the mean EtCO2 value in patients whosurvived was 34mmHg and the mean EtCO2 value in those who died was 25mmHg.Finally, there are the results of the last published article2 and HCO3¯, a weak correlation between EtCO2 and pH , and a weak correlation between EtCO2 and base excess by ABGanalysis .Among those studies focused directly on metabolic changes, it was found a study2 and PaCO2 is accepted regardless of age,-2and/or HCO3¯. Most of the studies show that capnography has proven to be a gold standard in theurgency and emergency settings, and its complementarity is evidenced along with pulseoximetry, in the monitoring of patients' breathing, circulation and metabolism. Inindividuals with normal lung function, a 2-5 mmHg gradient difference betweenEtCO,,-2 values andPCO2 or HCO3¯. These studies have all been performed on venous samples, which isconsistent because they have been carried out on child population and are less invasivetests. It is noteworthy that all studies on the pediatric population, both aimed at thedetection of DKA2 and venous CO2 pressure (PvCO2),should be greater than the gradient between EtCO2 and PaCO2, asthe mean difference between PaCO2 and PvCO2 is 6-8 mmHg (40mmHgPaCO2 vs 48mmHg PvCO2)-,2 is a valid and reliable system for use in the pediatricpopulation, and may even help to reduce costs, as it diminishes the blood tests,emphasizing that it is not possible to completely abolish the latter as reliable testsfor confirmation of the results. These results are considered as paradoxical because the differential physiologicalgradient between EtCO,-,-2 values. However, a good correlationwas found in previous studies,On the other hand, in the adult population, no correlation and/or concordance was foundbetween the study variables, discouraging the use of this system to assess the patient'smetabolic and/or ventilatory status, according to several studies2 and PaCO2,despite of using a Microstream and Mainstream system, indicating a good correlationbetween the measurements with the use of a Mainstream system, which may also be relatedto the results of a previous studySpecial attention should be given to the results of one of the studiesHaving the sensor near the airway seems to reduce the chance of mixing atmospheric air,just as Sidestream systems tend to increase dead space through the aspiration tube. Infact, in the conclusions of a study2 measurement, which makes itsreproducibility difficult and may lead to measurement imprecisions.On the other hand, based on another study,,2 values with mortality andlactate, indicating their use to predict mortality and the presence of septic status inthese patients. Studies focused purely on the detection of metabolic changes in adults), with a much extensive sample (n=1088), the same authors also found astrong correlation. In addition, they analyzed and compared the values of normal vitalsigns in relation to EtCO2, the latter parameter being the most predictiveand consistent value to indicate mortality in the outpatient environment, hence theydesignated it as the sixth vital sign. In this later workIn a later study2and HCO3¯ and between EtCO2 and PaCO2, especially inalkalotic patients. This is an important factor to be taken into account, since thephysiological compensatory response of metabolic acidosis is respiratory alkalosis,which can also occur in other common pathologies such as anxiety crisis.In future studies, correlations between the different groups of patients should bebetter analyzed according to the alkalosis or acidosis status of metabolic orrespiratory origin, since strong correlations have been found between EtCO2 values are influenced by variousphysiological factors, such as tissue metabolism, venous circulation, cardiac output,alveolar perfusion, and alveolar ventilation per minute2values, so there is the feasibility of getting low values, which are indicative ofacidosis, whereas the problem may be changes in the perfusion or ventilation rather thanmetabolism. In addition, it should be noted that EtCO2 values and severe symptomatology, itcan be assumed that he probably suffers from some severe pathology, which is causingthis alteration and will require emergency medical assistance. This may also be the caseof a patient with pulmonary thromboembolism, severe or respiratory heart failure,hemorrhagic shock, etc. For this reason, in several studies ,patients with cardiac, pulmonary or renal problems were excluded.According to the literature reviewed, it should also taken into account that in the caseof a patient with extremely low EtCO,-,) by means of a Receiver Operating Characteristic curve (ROC), findingaverage values, from 24.5 mmHg, the lowest, to 36 mmHg, the highest, as the upper cutoffpoint to rule out the possibility of acidosis. Values from 24.5 to 31 mmHg couldindicate the probability of acidotic status. As can be seen, the amplitude of the uppercutoff values was 11.5 mmHg, whereas the lower cutoff values show an amplitude less than6.5 mmHg between the values found. Due to the high variability in the data available upto now, it is not possible to recommend precise cutoff values for the use of thisparameter in clinical decision making.In general, it was observed a deficit in the control group with healthy patients in allthe studies assessed, lack of information on the measuring instruments and duration ofthe measurements, for example, eight studies did not specify the duration of themeasurements. The sample sizes were small and convenience sampling was used, as mostauthors indicated in their limitations. It is not possible to extrapolate the results inrelation to the measuring equipment because several capnograph models were used . All the2 andHCO3¯, or between EtCO2 and blood PCO2. Although furtherstudies are needed to evaluate these associations, it is possible to suggest that thescientific evidence supports the potential use of capnography as a new sign, biomarkeror complementary sentinel parameter to detect those patients with severe disease and itcan be easily implemented for use in spontaneous breathing patients. Most of the studies found results with a good correlation between EtCO2 values above 24.5-36 mmHg appear to exclude metabolic acidosisstatus, EtCO2 values less than 24.5-31 mmHg are indicative of acidoticstatus. Therefore, low capnography values, especially less than 24.5 mmHg in patientswith other signs or symptoms associated with some severe pathology, may indicate theneed for more specific tests and avoid delays in assistance, thus reducing morbidity andmortality in the emergency settings.While EtCO


Coexistence of hypertension, diabetes mellitus and chronic kidney disease synergistically aggravates the risk of cardiovascular and renal morbidity and mortality. These high-risk, multi-morbid patient populations benefit less from currently available anti-hypertensive treatment. Simultaneous angiotensin II type 1 receptor blockade and neprilysin inhibition (‘ARNI’) with valsartan/sacubitril (LCZ696) might potentiate the beneficial effects of renin-angiotensin-aldosterone inhibition by reinforcing its endogenous counterbalance, the natriuretic peptide system. This review discusses effects obtained with this approach in animals and humans. In animal models of hypertension, either alone or in combination with myocardial infarction or diabetes, ARNI consistently reduced heart weight and cardiac fibrosis in a blood pressure-independent manner. Additionally, LCZ696 treatment reduced proteinuria, focal segmental glomerulosclerosis and retinopathy, thus simultaneously demonstrating favourable effects on microvascular complications. These results were confirmed in patient populations. Besides blood pressure reductions in hypertensive patients and greatly improved (cardiovascular) mortality in heart failure patients, ventricular wall stress and albuminuria were reduced particularly in diabetic patients. The exact underlying mechanism remains unknown, but may involve improved renal haemodynamics and reduced glomerulosclerosis, e.g. related to a rise in natriuretic peptide levels. However, the assays of these peptides are hampered by methodological artefacts. Moreover, since sacubitrilat is largely renally cleared, drug accumulation may occur in patients with impaired renal function and thus hypotension is a potential side effect in patients with chronic kidney disease. Further caution is warranted since neprilysin also degrades endothelin-1 and amyloid beta in animal models. Accumulation of the latter may increase the risk of Alzheimer’s disease. Cardiovascular diseases cause nearly one third of all deaths worldwide , and 50%Treatment of high blood pressure greatly reduces the risk for all-cause mortality, coronary heart disease, heart failure and stroke. Development of renal failure, however, is not prevented by blood pressure lowering, and high-risk populations benefit less from this approach. Indeed, proportional risk reductions for major cardiovascular events are lower or absent in patients with concurrent diabetes or CKD . However1) receptor, thereby inhibiting Ang II-induced vasoconstriction, aldosterone release, stimulation of the sympathetic nervous system and vascular as well as cardiac remodeling . Th. Th25]. RAS blockade reduces cardiovascular and all-cause mortality as well as hospitalization for worsening heart failure in patients with reduced ejection fraction (HFrEF) . ACEi haAlmost 50% of heart failure patients have a preserved ejection fraction (HFpEF). RAS inhibition is less beneficial in this group of patients. Although it reduces the risk of hospitalization due to worsening of symptoms with 12%, there are no improvements in cardiovascular or all-cause mortality . Efficac2 and reduced eGFR (between 30 and 60 mL/min/1.73 m2) [2) [P = 0.11). These favourable outcomes might be explained by a reduction of renal tubulointerstitial fibrosis and focal segmental glomerulosclerosis, as observed in ARNI-treated diabetic, hypertensive rats when compared to ARB-treated controls [CKD patients are at high risk for cardiovascular morbidity and mortality, added on top of the risk of progression towards ESRD. Diabetes and hypertension are the most common causes of CKD worldwide and additionally independent risk factors for cardiovascular complications. Simultaneous presence of all three risk factors is not uncommon. However, the complex interplay between these diseases does appear to alter treatment responses. For HFrEF patients with renal function decline, regardless of cause and comorbidities, benefit of treatment with LCZ696 was equal for patients with eGFR ≥60 mL/min/1.73 m1.73 m2) . However1.73 m2) . Interes1.73 m2) . Further1.73 m2) •. Conver1.73 m2) , despite m2) [2) . Increas m2) [2) , 47, in  m2) [2) . No signcontrols . Moreovecontrols . These eDespite these potential advantages in renal outcome, there may be some limitations to the use of LCZ696 in CKD patients. Sacubitrilat is primarily eliminated by the kidneys. The degree of decline in eGFR correlated with increased maximum plasma drug concentration and half-life, as the percentage of sacubitrilat excreted in urine decreased progressively. Therefore, normotensive patients with moderate to severe renal impairment more often developed orthostatic hypotension . In PARA1-42). Intracerebral infusion of the NEP inhibitor thiorphan induces hippocampal accumulation and deposition of Aβ1-42 in rats, already at in vivo concentrations of 2.5 ng/mL [1-42 is believed to play a critical role in the development of Alzheimer’s disease . Blood-iewed in . After 2culation . Additiot manner . However1-42 accumulation and Alzheimer’s disease in populations with a longer median survival. Finally, we need additional insight into the mechanism of action of ARNI. Although a decrease in NT-proBNP and a rise in BNP have been reported [In summary, when compared to ARB, ARNI superiorly reduces blood pressure in uncomplicated, essential hypertension as well as in heart failure and CKD populations. When compared to ACEi, ARNI superiorly prevents death and hospitalization in HFrEF patients that already receive all other medication known to improve outcome. ARNI appears to improve renal outcome, particularly in high-risk, multi-morbid populations. Although patients with concomitant heart failure and diabetes show no reduction in mortality, they do demonstrate reverse left atrial remodeling, less heart failure hospitalization and reduced albuminuria. Preclinical data in hypertensive, diabetic rats additionally suggests blood pressure-independent improvement of renal damage, attested by decreased proteinuria and abated glomerulosclerosis. ARNI might mediate these effects by impeding activation of the proinflammatory cytokine TGF-β, which plays a central role in the fibrotic response and accumulation of collagen. This could explain the improved renal outcomes but requires further experimental study. Importantly, ARB and ARNI have not yet been compared in patients with CKD due to diabetes and hypertension, and thus the results of the HARP-III trial are anxiously awaited . Until treported , this mireported •. Anothereported . If so,


The goal of this study is to estimate the change in the relationships between use of five classes of antihypertensive medications and stages of Chronic Kidney Disease (CKD) in American adults treated for hypertension. The US National Health and Nutrition Examination Survey (NHANES) data sets 1999–2012 were used with the final analytical sample of 3,045 participants. Population prevalence estimates were calculated using the NHANES survey design weights. Inferential analyses were done with binomial logistic regression models.p = 0.0023) for users of ARB polytherapy and in users of ARB in patients with albuminuria (p = 0.0031). The odds of advanced  versus early CKD stages (1 and 2 combined) were significantly higher among patients treated with Angiotensin Receptor Blockers (ARB) versus those not treated with ARB in 2009–2012  = 2.52 (1.32–4.80)). From 1999 to 2012, the increase in this relationship was significant ( Aggressive pharmacological management of hypertension with ARB as add-on therapy may have accelerated kidney damage in American adults. However, prospective longitudinal studies are needed to establish proper temporal sequence in this relationship. Hypertension (HTN) is the second leading cause of kidney failure –7. Thus,This study examines the relationships between use of antihypertension medications and CKD stages among American adults (18 years or older) treated for hypertension and determines whether these relationships have changed from 1999 to 2012 . There was public health campaign during this time period to aggressively treat and lower blood pressure particularly by use of ACE I and ARBs in patients with CKD. We hypothesized that if the recommended treatment of hypertension in patients with CKD worked as intended then the associations with stages of CKD should be moving towards a decrease in the prevalence of advanced stages or at least stay stable; otherwise, the recommended therapy might appear to be more harmful than beneficial and should perhaps be revised.The US National Health and Nutrition Examination Survey (NHANES) is a representative sample of noninstitutionalized US civilian residents that are currently conducted every 2 years. NHANES data are obtained using a complex, multistage, cluster, and probability sampling design that incorporates differential probabilities of selecting participants. The data collection, reporting, and analyses followed consistent definitions that can be found on the websites .Three time points  were utilized to determine if these relationships have changed over time .Inclusion criteria were participants 18 years of age or older, who completed questionnaire and underwent a physical examination, reported demographic information , provided self-reported information on hypertension including treatment, had blood pressure measured, had estimated glomerular filtration rate (eGFR) and urine albumin/creatinine ratio (ACR), and were not pregnant if female. Population of interest was participants with hypertensive CKD, who satisfied inclusion criteria, and were treated for hypertension.CKD was defined by the level of glomerular filtration rate (GFR) and the urine albumin-to-creatinine ratio (ACR) , 18. TheHypertension for participants with CKD was present if systolic blood pressure is greater than or equal to 130 mm Hg or diastolic blood pressure greater than or equal to 80 mm Hg, or subject currently was taking medication to lower high blood pressure , 19.Treatment of high blood pressure was defined by an affirmative response to the question “Have you ever been told by a doctor or health professional that you had hypertension, also called high blood pressure?” and to the following questions: “Because of your high blood pressure/hypertension, have you ever been told to take prescribed medicine?” and “Are you now following this advice to take prescribed medicine?” , 19.Diabetes was present if glycohemoglobin (HbA1c) was equal to or greater than 6.5% .β-blockers); (4) CCB ; and (5) Diuretics [The five antihypertensive classes of medications were (1) ACE I (Angiotensin Converting Enzyme Inhibitors); (2) ARB (Angiotensin Receptor Blockers); (3) BB (rs); and  Diureticiuretics . MonotheData from seven NHANES surveys 1999–2012 included 71,916 records. The analytical sample of hypertensive participants with CKD who were treated for HTN and satisfied inclusion criteria was 3,045; see consort flow diagram, ∗) in the tables [The prevalence of CKD by classes of antihypertensive medications was age-standardized to the 2000 US standard population using 4 age groups , 21. Varα/k was used where k is the number of analyses.Binomial logistic regression models were used to test the hypotheses of the study. In the models for three time points , the ordinal coded dichotomous variable for stages of CKD was the dependent variable (outcome), time was independent variable, and class of antihypertensive medication was the independent variable (effect modifier). Interaction terms (time × class of medication) or (time × mono- or polytherapy) were used to test the null hypothesis of no difference in change in the odds ratios for patients treated versus untreated with particular class of medication over 14-year time period. The models included the following covariates: age, gender, race/ethnicity, body mass index (BMI), smoking status, diabetes, and albuminuria to adjust for potential confounding. The models accommodated the complex multistage sample survey design following NHANES Analytic and Reporting guidance . To presTrend was determined with the statistically significant interaction between class of medication and time  indicating that their relationships had changed over time. In the models, the outcome variable was modeled as Logits that contrasted advanced  with the earlier (1 and 2 combined) stages of CKD. The odds ratios  were reported for each of five classes of medications: ACEI, ARB, BB, CCB, DIU, and poly- or monotherapy.Exploratory Analyses. Subgroup analyses were performed with the same model and covariates for the following groups: diabetes (absent/present); albuminuria/ACR >30 mg/g (absent/present); microalbuminuria/ACR 30–<300 mg/g (absent/present); macroalbuminuria/ACR >300 mg/g (absent/present); diabetes with albuminuria; diabetes with microalbuminuria; diabetes with macroalbuminuria; diabetes without albuminuria; diabetes without microalbuminuria; diabetes without macroalbuminuria; no diabetes and albuminuria; no diabetes and microalbuminuria; no diabetes and macroalbuminuria.Statistical analyses were conducted using the SAS® System for Windows  and utilized the SURVEY procedures that account for NHANES survey multistage complex design .The use of medications other than the five major classes decreased from about 6.5% in 1999–2004 to 4.6% in 2005–2008 and 3.9% in 2009–2012. Those “other” included miscellaneous cardiovascular agents, vasodilators, vasopressors, agents for pulmonary hypertension, aldosterone receptor antagonists, and renin inhibitors; and they were not considered in this study. The use of alpha-1 blockers increased from 4.27% in 1999–2004 to 5.44% in 2005–2008 and 6% in 2009–2012. Similarly, the use of central alpha-2 antagonists and other centrally acting antiadrenergic agents increased from 3.58% in 1999–2004 to 3.81% in 2005–2008 and 5.28% in 2009–2012. This study did not examine alpha-blockers, but focused only on the use of five major classes of antihypertensive medications recommended by JNC-7 to treat hypertension in patients with CKD [From 1999 to 2012, the prevalence % (SE) of adults with CKD and HTN who were treated for HTN increased from 55.58% (1.81) to 64.76% (1.91). Among five classes of medications, the use of ARB polytherapy increased the most: from 12.26% (1.44) to 21.56% (2.22); and the use of DIU polytherapy decreased the most: from 49% (2.55) to 42.05% (2.35); from 1999–2004 to 2009–2012. Two out of three patients with CKD and HTN received combination of classes .The prevalence of users of more than one class decreased from 65.76% (2.24) to 62.21% (3.31); however, the distributions by CKD stages for these users demonstrated increase in advanced stages, from 55.45% (2.28) to 56.20% (3.59) in stage 3 and from 7.33% (1.62) to 8.97% (1.85) in stages 4 and 5 combined, and decrease in early stages (1 and 2) from 37.21% to 34.82% . The prep = 0.0069), users of ARB polytherapy (p = 0.0023), and for users of poly- versus monotherapy (p = 0.0063); see p = 0.0065). However, complete analysis cannot be performed, particularly for ARB combinations with ACEI due to small sample sizes.The significant increase in the odds of advanced versus early stages was observed for ARB users (α/15 = 0.0033 (Bonferroni correction for α = 0.05) where 15 is the number of analyses. The same models stratified by subgroups demonstrated significant increase in odds of advanced versus early stages of CKD for: (1) ARB users among patients with albuminuria (p = 0.0031) and (2) users of more than one class of medications with albuminuria (p = 0.002); table is not present.The exploratory analyses were conducted with level of significance p = 0.0023) from 1999 through 2012. The trend can be explained by the increase in prevalence of advanced stages CKD and decrease or stable prevalence in early stages among users of ARB polytherapy. Such increase in advanced CKD stages may have been explained by use of ARB combinations with ACEI that was particularly warned by JNC-7, but those combinations were least prevalent and decreased during the investigated time period. Possibly, change in the relationship was driven by ARB combinations with other classes, particularly with CCB where odds of advanced stages significantly increased compared to the odds of earlier stages, from 1999 through 2012. A significant increase in advanced stages was observed for ARB users among people with albuminuria. The results suggest that increase in ARB polytherapy may have increased advanced stages of CKD among American adults, particularly among people with albuminuria.The major finding is that there was significant increase in this relationship for the users of ARB polytherapy (p = 0.03) increase in unadjusted prevalence of users of multiple antihypertensive drugs in this population of adults with CKD from 54.2% (3.5) to 65.6% (3.0), from 2001-2002 to 2009-2010 [In this study for American adults 18 years or older with CKD, the changes in age-standardized prevalence were from 55.58% to 64.76%, from 1999–2004 to 2009–2012 . Gu et a009-2010 . But the009-2010 . In the 009-2010 . The aut009-2010 .The current study is the first study to the authors' knowledge that estimated changes in relationships between use of antihypertensive medications and stages of CKD for American hypertensive adults with CKD. The results are consistent with the population-based ecological study in the United Kingdom and suggest that significant increase in advanced stages of CKD can be potentially attributable to the treatment with ARB polytherapy, perhaps, damaging the kidney and increasing albuminuria. However, the temporal relationship between ARB therapy and increase in advanced stages of CKD cannot be established because of the cross-sectional nature of this study. It is possible that increase in ARB therapy resulted from the increase in advanced stages of CKD. Prospective longitudinal studies are needed to establish proper temporal sequence of this relationship.The major limitation is that cross-sectional NHANES data does not allow assessing the relationship between CKD and treatment of hypertension longitudinally within patients. Another limitation is that blood pressure was measured on a single day versus on more than two separate days as was recommended by JNC 7 guidance . HoweverThe link between ARBs and acute kidney injures was recognized recently by KDIOGO and UK National Institute for Health and Clinical Excellence (NICE) , 24. The