Primary aldosteronism (PA) is a potentially curable form of secondary hypertension caused by excessive renin-independent aldosterone secretion, leading to increased target organ damage and cardiovascular morbidity and mortality. The diagnosis of PA requires measuring renin and aldosterone to calculate the aldosterone-to-renin ratio, followed by confirmatory tests to demonstrate renin-independent aldosterone secretion and/or PA subtype differentiation. Various antihypertensive drug classes interfere with the renin-angiotensin-aldosterone axis and hence evaluation for PA should ideally be performed off-drugs. This is, however, often precluded by the risks related to suboptimal control of blood pressure and serum potassium level in the evaluation period. In the present review, we summarized the evidence regarding the effect of various antihypertensive drug classes on biochemical testing for PA, and critically appraised the issue whether and which antihypertensive medications should be withdrawn or, conversely, might be continued in patients evaluated for PA. The least interfering drugs are calcium antagonists, alpha-blockers, hydralazine, and possibly moxonidine. If necessary, the testing may also be attempted during treatment with beta-blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers but renin and aldosterone measurements must be interpreted in the context of known effects of these drugs on these parameters. Views are evolving on the feasibility of testing during treatment with mineralocorticoid receptor antagonists, as these drugs are now increasingly considered acceptable in specific patient subsets, particularly in those with severe hypokalemia and/or poor blood pressure control on alternative treatment. Primary aldosteronism (PA) is a potentially curable form of secondary hypertension caused by excessive renin-independent aldosterone secretion. Patients with PA have a higher risk of target organ damage and cardiovascular morbidity and mortality compared to matched subjects with essential hypertension and the same blood pressure values . Excess The classical clinical picture of PA includes hypertension and hypokalemia. While hypertension is almost always present in subjects with PA, plasma potassium levels are frequently within normal limits. Data from the recent studies show that less than 50% of patients present with hypokalemia, more often subjects with APA than with bilateral hyperplasia. The blood pressure in PA is usually substantially elevated, in particular in patients with APA. In a retrospective analysis of patients with resistant hypertension, 182 (11.3%) of cases of PA were identified , but PA The initial evaluation should consist of the measurement of plasma aldosterone concentration (PAC) and renin (plasma renin activity [PRA] or direct renin concentration [DRC]) to demonstrate reduced PRA with an inappropriately high level of plasma aldosterone. The aldosterone-to-renin ratio (ARR) has been commonly accepted as a screening test for PA and a value above 20 (if PAC is expressed in ng/dL and PRA is expressed in ng/mL/h), when accompanied by elevated PAC, is considered abnormal, suggesting renin-independent aldosterone excess. To confirm the diagnosis of PA, inappropriate secretion of aldosterone should be demonstrated with maneuvers that reduce renin-dependent aldosterone secretion. Usually, excessive sodium loading, orally or by the intravenous infusion, is used. Less common tests include suppression with synthetic mineralocorticoid fludrocortisone or captopril challenge test. When the diagnosis of PA is confirmed, adrenal computed tomography (CT) is recommended to differentiate between unilateral and bilateral lesions. Many experts recommend that patients with PA referred for surgery should undergo adrenal venous sampling (AVS) before adrenalectomy. This is related to the limitations of adrenal CT which frequently does not detect small adenomas in a contralateral gland or cannot distinguish between functioning or non-functioning adenomas.Measurement of ARR in patients with different forms of hypertension does not detect a distinct population of subjects with PA characterized by an elevated ratio. ARR abnormality was defined using different criteria, like the response to surgical treatment, results of suppression tests or comparison to the range seen in normal subjects. In the wide range of hypertensive subjects, ARR represents a continuous variable and cut-off values are defined arbitrarily. This may represent the continuum of renin-independent aldosteronism which also contains subjects with mild-to-moderate hypertension. The systematic review by Kaiser et al. which included 39 studies with over 42,000 patients reported the estimates of prevalence of PA ranging from 3 to 13% in the primary care and 1–30% in specialized centers . Recent To avoid false-positive and false-negative results of biochemical tests, certain conditions must be met. The guidelines recommend to collect blood samples for ARR in the morning after patients have been out of bed for at least 2 h, usually after they have been seated for 5–15 min. The patient should not restrict salt intake before testing and should be potassium-replete. Many drugs interfere with the renin-angiotensin-aldosterone axis  and ideaThe need to withdraw some or most antihypertensive medications before testing for PA prolongs the overall diagnostic process, often by many weeks, and limits the feasibility of testing in patients with more severe/resistant hypertension or with a very high cardiovascular risk, e.g., after a recent cardiovascular event, in whom withdrawing all or some medications is deemed unsafe. On the other hand, testing while on antihypertensive medications creates issues with the interpretation of renin and aldosterone measurements for the purpose of diagnosing PA due to the effect of these medications on the biochemical parameters being measured.Indeed, it has been recently shown in a large cohort study in the United States that testing for PA is rare in patients with resistant hypertension, but if the testing was performed, it was associated with a higher likelihood of initiating mineralocorticoid receptor antagonist (MRA) therapy and better blood pressure control over time .The goal of the present review is to summarize the evidence regarding the effect of various antihypertensive drug classes on biochemical testing for PA, and critically appraise the issue whether and which antihypertensive medications should be withdrawn or, conversely, might be continued in patients evaluated for PA. Based on the available data, we propose an approach to antihypertensive drug regimen modifications when screening for PA.The aldosterone-to-renin ratio was proposed as a screening test for PA by Various antihypertensive drugs alter renin activity (or concentration) and/or aldosterone secretion, influencing the ARR  Table 2Table 2.Beta-adrenergic blockers and central antagonists increase plasma aldosterone levels and decrease renin levels, thus increasing ARR and leading to false positive results . Newer sDiuretics stimulate renin more than aldosterone secretion, causing falsely negative ARR values , while dAngiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) increase renin and decrease PAC and, therefore, lower the ARR. In patients with PA, ACEI appear to be much less able to stimulate PRA than in those without PA, and are therefore unlikely to cause a false negative ARR . The effThe current guidelines state that a washout of all interfering antihypertensive medications before ARR testing is feasible in patients with mild hypertension but it is potentially problematic in others . TherefoThe effect of different drug therapies on ARR has rarely been systematically evaluated in prospective studies . Gallay Seifarth et al. analyzed PAC and DRC in 37 normotensive controls, 144 hypertensive patients with essential hypertension and 19 patients with PA on single drug or combination therapy with beta-blockers, ACEI, ARB, calcium antagonists, spironolactone, or no treatment . In patiMulatero et al. in their classical randomized study investigated the effects of therapy with atenolol, amlodipine, doxazosin, fosinopril, and irbesartan on the ARR in a group of 230 patients with suspected PA based on screening ARR >50 with PAC >10 ng/dl . PatientA recently published prospective study performed in 42 consecutive patients with an unambiguous diagnosis of PA evaluated whether ARR values were affected by the MRA canrenone and/or by canrenone plus olmesartan treatment in patients with PA . PatientThe results discordant with the above were recently obtained in a retrospective cohort study in 146 patients with hypertension, including 91 with PA, who had plasma aldosterone and renin measurements before and after initiation of MRA treatment . InitiatAccording to the Endocrine Society, confirmatory tests are considered mandatory for the definite diagnosis of PA . These rSalt loading test is usually performed by either direct salt loading or intravenous salt infusion. During direct salt loading, the patient should receive approximately 6 g of salt daily (>200 mmol) for 3 days. Then, both aldosterone and sodium excretion should be assessed in a 24 h urine collection. A urinary aldosterone excretion <10 μg/24 h (28 nmol/d) indicates a low probability of PA, while a result >12 μg/24 h (>33 nmol/d) supports its diagnosis. The saline infusion test is usually performed in the morning in a patient remaining supine for 1 hour prior to testing. Then, over a 4 h period, 2 L of 0.9% saline are administered with careful blood pressure and heart rate monitoring. Blood samples for renin, aldosterone, cortisol and potassium determination are drawn at 0 and 4 h. A post-infusion PAC <5 ng/ml (140 pmol/L) decreases, while PAC >10 ng/ml (280 nmol/L) increases the probability of PA. It should be stressed that the saline infusion test may be not reliable due to failure to sufficiently differentiate between subjects with primary hypertension and normokalemic patients with PA .Both the above tests should be performed under careful medical supervision. Due to significant sodium and fluid overload, these tests are not recommended in subjects with uncontrolled hypertension, left ventricular failure and renal insufficiency and marked hypokalemia.During the fludrocortisone suppression test, the patient receives 0.1 mg of fludrocortisone every 6 h for 4 days. Additionally, potassium chloride supplementation and a high-sodium diet are necessary to maintain the appropriate plasma potassium concentration and ensure adequate urine sodium excretion. Plasma aldosterone and renin activity should be measured at 10 AM and cortisol at 7 and 10 AM on the last day of the test. The diagnosis of PA can be confirmed when the PAC of >6 ng/dl is accompanied by PRA <1 ng/mL/h and the cortisol concentration is lower at 10 AM than at 7 AM.The captopril challenge test consists of administering 25–50 mg of captopril orally to the patient sitting or standing for 1 h. In patients with PA, PAC remains increased at suppressed PRA. The test is easily performed and safe for patients who are at risk due to compromised renal or cardiac function .As confirmatory tests are performed after the initial diagnosis of PA including ARR measurement, the recommendations regarding the use of various antihypertensive drugs during testing are the same as before determination of ARR.If it is possible based on the patient’s clinical status, i.e. blood pressure values, MRA should be withdrawn for at least 4 weeks while other antihypertensive drugs should be withdrawn for at least 2 weeks before testing. Replacement of other antihypertensive drugs with calcium antagonists or alpha-blockers may minimize interference with aldosterone and renin measurements. In one study, the effect of chronic antihypertensive medications on confirmatory testing results was investigated . The stuImportantly, some authors question the utility of confirmatory testing, instead suggesting proceeding directly to PA subtype determination by AVS if the patient is a candidate for surgery to remove APA. According to the Italian authors , the useAccording to the 2016 Endocrine Society guidelines, ARR remains the first line (screening) test for the evaluation for PA. If ARR is abnormal (elevated), a confirmatory test is needed, except for patients with spontaneous hypokalemia, plasma renin below the detection threshold and plasma aldosterone >20 ng/dl .It is generally recommended to measure ARR after discontinuation of drugs that might affect renin and/or aldosterone. While it may be easily done in patients with mild hypertension, withdrawal of antihypertensive drugs may lead to suboptimal blood pressure control for several weeks in patients with more severe hypertension, with potential adverse consequences. The risks of modifying antihypertensive medication programs include hypertensive crisis, severe hypokalemia, atrial fibrillation, and heart failure. In one study, it was shown that withdrawal of the interfering drugs was possible in only half of patients, and 12% of them had a serious event necessitating hospital admission .Thus, an important question arises which drugs should be discontinued and which may be used for blood pressure control during the testing period.Beta-blockers and central agonists  decrease renin and increase aldosterone, thus artificially elevating ARR. Potassium-wasting and -sparing diuretics increase renin more than aldosterone, and thus artificially decrease ARR. Spironolactone was shown to significantly increase renin and reduce ARR in an older study , and theOverall, the conclusions from the studies that specifically evaluated whether ARR measurement and diagnostic interpretation are affected by ongoing treatment with various antihypertensive drug classes vary. In summary, studies consistently show that diuretics artificially decrease ARR , while beta-blockers and central agonists artificially elevate ARR, which may increase the rate of false-positive ARR results. Conclusions regarding the feasibility of measuring ARR on ACE/ARB vary, while calcium antagonists , alpha-blockers and moxonidine are not interfering much with ARR measurement and thus may be continued.Regarding the feasibility of measuring ARR during MRA treatment, this issue seems more complex. The finding by the Rossi group that canrenone did not preclude an accurate diagnosis in patients with PA, is at variance with previous thinking and statements that MRA should be withdrawn before ARR measurement . HoweverOverall, the above study findings are largely reflected by the recommendations regarding drug withdrawal for ARR measurement included in the 2016 Endocrine Society guidelines .According to the 2016 Endocrine Society guidelines, aldosterone antagonists, other potassium-sparing diuretics, and potassium-wasting diuretics markedly affect ARR and should be withdrawn for at least 4 weeks. Of note, some other older guidelines suggested withdrawal of these drugs for a longer time, even 6 weeks or longer . If ARR The authors of the 2020 Italian guidelines  agree thImportantly, as noted above, the two recently published Italian guideline documents  allow usOur recommendation for the extent and order of drug withdrawal for ARR measurement would be thus as follows .If hypertension is not very severe and it may be expected to be reasonably controlled on two or three medications, an attempt could be made to replace the existing regimen with a combination of a calcium antagonist and an alpha blocker, potentially with an addition of a third non-interfering drug . Regarding the choice of a calcium antagonist, verapamil could be preferentially used  but a diIf for some reasons such an antihypertensive drug regimen switch is deemed not feasible , only diuretics should be stopped  for 4 weeks, and the patient may be left on a regimen that includes beta-blocker, calcium antagonist, ACEI/ARB, and alpha-blocker if needed.As noted above, recent data indicate that MRA may not need to be discontinued before testing for PA, but we believe, as noted in the recent Italian guidelines , that coFollowing these antihypertensive drug regimen modifications, ARR is measured but renin and aldosterone measurements should be interpreted in the context of known effects of these drugs on ARR . Only ifWhen this alternative approach to perform ARR measurement on interfering antihypertensive drugs is pursued, the renin and aldosterone measurements must be interpreted taking into account the known effects of these drugs on ARR. In these settings, it is particularly important to look not only at the calculated ARR value, but also consider renin and aldosterone measurements separately. In particular, if ARR is elevated but this elevation is solely due to low renin with low normal aldosterone, a false-positive result is likely. For that reason, some authors recommend that elevated ARR value should be interpreted as abnormal only in conjunction with a certain threshold plasma aldosterone level. However, the threshold of PAC >15 nd/dl proposed by some authors  may resuIf necessary, most antihypertensive medications can be continued. For example, although beta-blockers lower renin and raise ARR, the increased ARR is not clinically important in this setting because of the low PAC (<10 ng/dl) in patients without PA .ACEI and ARB elevate renin and reduce PAC, leading to a risk of a false-negative ARR. Therefore, a high renin (PRA >1 ng/mL/h or high DRC) in a patient treated with ACEI/ARB does not exclude PA. On the other hand, low renin (PRA <1 ng/mL/h or low DRC) in a patient taking one of these drugs is a strong predictor for PA. Hence, discontinuation of these medications is often not necessary but repeat assays must be performed off-treatment if renin is found to be high during on-drug testing .Similar interpretation applies to testing on MRA. In specific situations, for example in some patients with severe PA, as discussed above, aldosterone and renin may be measured in patients treated with MRA, and if renin is suppressed, these medications are not interfering, particularly if used in low doses). Hence, if renin is found to be suppressed, further testing (including confirmatory testing and AVS) can be performed without discontinuing MRA. However, if renin is not suppressed, then MRA therapy should be discontinued for 4–6 weeks before retesting.Our recommendations regarding antihypertensive drug withdrawal before a confirmatory test would be generally consistent with the above recommendations regarding drug treatment modifications before ARR measurement. The authors of the 2016 Endocrine Society guidelines recommended that clinicians utilize the pharmacological agents with minimal or no effects on the renin-angiotensin-aldosterone system, and should avoid medications known to stimulate renin during confirmatory testing because these prevent the suppression of aldosterone . Thus, it would be best to limit the antihypertensive treatment to calcium antagonists (particularly verapamil), alpha-blockers, moxonidine and/or hydralazine, while diuretics and ACEI/ARB should be avoided. In the light of the recent data, MRA could be used if necessary, as long as renin is shown to be suppressed.For practical reasons, if ARR is first performed on some interfering medications and then a decision is made to withdraw these medications anyway due to difficult interpretation of the ARR measurement, it might be reasonable to perform the repeated ARR measurement along with a confirmatory test, such as intravenous saline loading . This would require withdrawal of antihypertensive medications only once and/or for a shorter period, in contrast to a situation, e.g., where ARR is re-measured first on an outpatient basis and only later a decision is made to perform further inpatient testing (a confirmatory test and/or AVS).Research gaps and potential developments in the field. The effect of antihypertensive medications on ARR was evaluated in various populations including healthy volunteers, patients preselected according to ARR or in patients with confirmed PA only. The medication regimens, e.g., one or two drug combinations, as well as specific drugs did not necessarily reflect well the usual/current clinical practices in the management of hypertension. In addition, the cut-off values for positive ARR were higher than commonly accepted in the clinical practice. Thus, more studies, including prospective and randomized ones, are needed, as well as studies in larger patient populations. In particular, more studies are needed that would be based on lower cut-off values for positive ARR and that would evaluate the effects of antihypertensive drugs in various patient subsets, e.g., general population of patients evaluated for PA, in contrast to patient populations with an established diagnosis of PA or even “florid” PA phenotype in which many studies discussed in this review were performed.Discordant data are available regarding the reproducibility of ARR . VariatiBased on the recent literature, there are discordant/evolving conclusions regarding the feasibility of MRA use during testing , as oppoA relatively “novel” approach of bypassing a confirmatory test and proceeding directly to AVS  also reqTesting for PA should be ideally performed off-drugs that interfere with the renin-angiotensin-aldosterone axis. However, the need to withdraw these drugs and/or modify the treatment accordingly for several weeks prolongs the overall diagnostic process, and the feasibility of testing in patients with more severe/resistant hypertension, very high cardiovascular risk, or severe hypokalemia is limited due the risks related to suboptimal control of blood pressure and serum potassium level in the evaluation period. On the other hand, testing while on interfering antihypertensive medications creates issues with the interpretation of renin and aldosterone measurements for the purpose of diagnosing PA due to the effect of these medications on the measured parameters. Our literature review indicates that the least interfering drugs are calcium antagonists, alpha-blockers, hydralazine, and possibly moxonidine. If necessary, the testing may also be attempted during treatment with beta-blockers, ACEI, and ARB but renin and aldosterone measurements must be interpreted in the context of known effects of these drugs on these parameters. Views are evolving on the feasibility of testing during treatment with MRA, as these drugs are now increasingly considered acceptable in specific patient subsets, particularly in those with severe hypokalemia and/or poor blood pressure control on alternative treatment.


The present paper will provide an update on the role of sympathetic neural factors in the development and progression of essential hypertension by reviewing data collected in the past 10 years. This will be done by discussing the results of the published studies in which sympathetic neural function in essential hypertension and related disease has been investigated via sophisticated and highly sensitive techniques, such as microneurographic recording of sympathetic nerve traffic and regional norepinephrine spillover. First, the relevance of the pathophysiological background of the neurogenic alterations will be discussed. It will be then examined the behavior of the sympathetic neural function in specific clinical phenotypes, such as resistant hypertension, pseudoresistant hypertension, and hypertensive states displaying elevated resting heart values. This will be followed by a discussion of the main results of the meta-analytic studies examining the behavior of sympathetic nerve traffic in essential hypertension, obesity, metabolic syndrome, and chronic renal failure. The sympathetic effects of renal denervation and carotid baroreceptor stimulation as well as the possible involvement of sympathetic neural factors in the determination of the so-called “residual risk” of the treated hypertensive patients will be finally discussed. American Journal of Hypertension of our state-of-the-art paper on the sympathetic nervous system (SNS) in hypertension,1 several studies have been published allowing to considerably expand our knowledge in the field and to strengthen some new concepts that 11 years ago were making their initial steps in the world of the SNS in hypertension.Since the publication in 2010 in the The goal of this paper is to provide a critical overview of the new findings, new concepts, and future directions of the research targeted on SNS in hypertension. The roadmap of the journey will include the following stages. First, we will provide a brief summary on what we regard as well established notions on SNS in hypertension. We will then examine the evolution of the new concepts on the pathophysiology of the SNS activation in the high blood pressure state, highlighting the relevance of the immune system and the inflammatory process in the development of the adrenergic overdrive, but also discussing the potential role of genetic and other factors which directly or indirectly may exert sympathoexcitatory effects. A further step will be to describe the main features of the SNS in resistant hypertension, a clinical condition which became in the past years an area of intense investigation. During the last decade, a consistent amount of interest has been focused on heart rate as potential sympathetic marker, given the evidence that the latest European guidelines on hypertension have recognized the importance of elevated heart rate values as an independent cardiovascular risk factor. Another important step of the long journey will be represented by the results of major meta-analyses recently published aimed at providing conclusive information on how hypertension and other comorbidities may affect the SNS. The last stage of the journey will be devoted to (i) the analysis of the data obtained in the past decade on the involvement of the SNS in the blood pressure effects of bilateral renal nerves ablation (as well as of other invasive approaches) and (ii) the possibility that the so-called “residual risk” displayed by treated hypertensive patient may be at least in part linked to the behavior of the sympathetic responses to antihypertensive drugs.2 Second, different clinical phenotypes of hypertension  display as a common feature the SNS activation.3 Third, one of the major drivers of the adrenergic overdrive is the 24-hour blood pressure load, which in several clinical conditions appears to be related to the sympathetic function more closely than clinic blood pressure.3 Fourth, the detection of associated target organ damage  is accompanied by a further sustained increase in the sympathetic cardiovascular drive.3 Fifth, not only organ damage but also associated clinical conditions, such as obesity, obstructive sleep apnea, metabolic syndrome, congestive heart failure, and renal failure, may further potentiate the already elevated adrenergic cardiovascular drive detected in uncomplicated essential hypertension.3 Some other well-defined aspects of the neuroadrenergic activation are worthy of mention. These include the evidence that different organs  share the hyperadrenergic state, as elegantly documented by the regional norepinephrine spillover technique.4 In addition, a number of humoral and reflex mechanisms contribute at the pathophysiology of the neurogenic alterations, which thus appear to have as background a multifactorial nature.4 Finally, conclusive evidence has been provided that the SNS alterations are not irreversible, but they can be modulated by pharmacological and nonpharmacological interventions currently employed in the therapeutic approach to the hypertensive state.5As shown in The last decade has seen the development of new concepts in the pathophysiological background leading to the neuroadrenergic overdrive in hypertension. These in particular include 3 areas.7 Evidence has been accumulated, particularly in essential hypertension, that the relationships between the immune system and SNS are bidirectionally interactive.8 Concerning the role of the SNS as triggering mechanism of the interaction, demonstration has been provided that (i) an increase in sympathetic activity elicits T-lymphocytes activation and vascular inflammation,9 (ii) significant correlations have been found between circulating plasma norepinephrine and interleukin-6 produced by T-lymphocytes as well as tumor necrosis factor-alpha produced by macrophages and monocytes,10 and (iii) chronic SNS activation desensitizes lymphocyte β 2-adrenoceptors, thereby altering the immune function.10 On the other hand, inflammation and T-lymphocyte activation, which are both triggered by oxidative stress,11 may favor a sympathetic activation.12 In any case proinflammatory substances and mediators may trigger signal to the central nervous system activating the sympathetic neurogenic component.12 The evidence on a direct role of inflammatory and immune factors in the development and/or in the progression of hypertension-related sympathetic activation is still lacking in human beings. Recently, however, some evidence confirming the importance of the inflammatory process in the neuroadrenergic activation has been provided in patients affected by rheumatoid arthritis, in which sympathetic nerve traffic recording displayed a level of neuroadrenergic activation greater for magnitude than the one detected in age-matched healthy controls.13 The SNS overdrive was also significantly potentiated when rheumatoid arthritis was detected in hypertensive patients.13The first one refers to the role of immunologic and inflammatory factors, whose importance in the development of the neuroadrenergic activation received in recent years growing experimental support. The current knowledge on this participation can be summarized as follows. An increased number of studies have shown that immune mechanisms play a primary role in the pathophysiology of essential hypertension by contributing via the participation of macrophages and immune competent cells at the inflammatory state which characterizes not only hypertension but the atherosclerotic vascular process and congestive heart failure.14 Evidence has been provided that both in experimental animals and in humans this gene participates at the development of some forms of high blood pressure, such as those related to stress.15 In gene association studies evidence has been provided that subjects homozygous for the G allele of a phosphoducin single nucleotide polymorphism display greater blood pressure and sympathetic values than those found in humans with the A allele.15 Other studies have shown that subjects with a deficiency in genes encoding the melanocortin-3 and -4 receptors are characterized by low blood pressure and hemodynamic and biochemical signs of a reduced sympathetic tone.16 Conversely, genetic variations in neuropeptide Y receptors as well as in renalase activity appear to be associated with high blood pressure.17 Two final evidences further strengthen the role of genetic background in determining the sympathetic neural activation. Indeed in a study performed by our group we have shown that in hypertensive patients with metabolic syndrome, SNS overdrive is linked to the gene encoding the alpha1A adrenoceptor.18 Similarly, Australian investigators have provided evidence that a single nucleotide polymorphisms in the norepinephrine transporter gene is linked to elevated circulating plasma levels of norepinephrine and elevated systolic (but not diastolic) blood pressure.19 Taken together, the findings suggest that some hypertensive clinical phenotypes may be characterized by a genetic background that is linked to the sympathetic neural abnormalities, thereby favoring the development with time of the elevated blood pressure values.The second area of intense research in the field of the mechanisms of the sympathetic overdrive in hypertension refers to the contribution of genetic factors as potential triggers for the neurogenic alterations. In particular some specific genes have been identified. These include, for example, the phosphoducin gene, which is a regulator of G-protein-mediated signaling and is known to be present in several tissues, including the central nervous system and the sympathetic ganglia.20 The unique feature of the study was represented by the sympathetic nerve traffic evaluation which was performed in these patients via the microneurographic technique before and after iron depletion therapy. Results provide strong evidence on the concept that iron overload is characterized by a hyperadrenergic state which is almost completely reversed by iron depletion. Recently, information on the role of iron, and specifically body iron overload, in the determination of the adrenergic overdrive typical of hypertensive state have been implemented, with the evidence that essential hypertensive patients with iron overload display sympathetic nerve traffic values significantly greater than the ones detected in uncomplicated hypertensives, for similar age and 24-hour blood pressure loads.21 This finding, strengthened by the significant relationships found in our study between muscle sympathetic nerve traffic, serum ferritin, transferrin saturation, and hepatic iron load, supports the hypothesis that iron “per se” is an organic metallic compound capable to exert sympathoexcitatory properties. Evidence has been indeed provided that iron is involved in a number biological steps that may directly or indirectly enhance sympathetic cardiovascular drive, including baroreflex alterations, vascular inflammation, immune reactivity, development of an oxidative stress process, and a nitric oxide crowing.A further step forward in assessing the complex interrelationships between genetic factors and the SNS function comes from the studies which recently assessed microneurographic recording of efferent postganglionic sympathetic nerve traffic in patients with genetic hemochromatosis, the most common human model of primary iron overload.22 This is the case also for the involvement of SNS in the disease development and progression. An early study based on norepinephrine spillover assessment in 10 patients with resistant hypertension undergoing renal denervation has documented an increase in renal sympathetic drive, which has been more recently confirmed in a larger patients sample.23 More direct information on the patterns of the SNS in resistant hypertension come from data collected by our group in the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) project, an epidemiological study carried out in a large sample of the general population living in the surroundings of the north Milan urban area.24 The aim of this specific substudy was to assess indirectly or directly the behavior of the adrenergic neural influences on the heart and peripheral circulation in resistant hypertensive patients.25 In the first set of studies, we examined the 2 cyclic components of systolic and diastolic blood pressure residual variability identified via a fast Fourier transform spectral analysis of the ambulatory blood pressure tracing. The first of these 2 components has been shown to be closely related to muscle sympathetic nerve traffic values, for both the systolic and the diastolic blood pressure components. When this analysis was applied to a selected group of hypertensive patients from the PAMELA study, we found that this first component was significantly greater in the case of systolic blood pressure in resistant hypertensives compared with the values seen in controlled and uncontrolled hypertensives, i.e., patients in which antihypertensive drug treatment was able or unable, respectively, to reduced blood pressure below 140/90 mm Hg  of the adrenergic activation in resistant hypertensive patients as compared with age-matched nonresistant hypertensives and true normotensives. Of interest was the finding that spontaneous baroreflex sensitivity was significantly impaired in resistant hypertensives, which also displayed a significant relationship between muscle sympathetic nerve traffic values, anthropometric data, and plasma aldosterone levels.26 Similar findings were observed in 2 other studies performed in resistant hypertensive patients.28 In a more recent microneurographic study we further investigated the issue, by examining whether and to what extent true resistant hypertension displays a SNS profile different from the one seen in apparent or pseudoresistant hypertension, i.e., patients in which careful examination revealed that the poor blood pressure control was not dependent on a resistant blood pressure state but rather by a poor compliance and adherence to treatment.29 This latter clinical condition is remarkably different from the true resistant hypertensive state and depends on multiple and heterogeneous causes, including inadequate blood pressure measurements, nonadherence to treatment as well as presence of a white-coat effect. The microneurographic data collected by our group strongly support the notion that also the behavior of SNS is consistently different in these 2 clinical conditions. Indeed, at variance from the true resistant hypertensive state, apparent resistant hypertension does not display any sign of cardiac or peripheral sympathetic overactivation, the resulting neuroadrenergic profile being thus indistinguishable from the one characterizing the true normotensive state.29 In reviewing the data collected during the last decade on the topic related to the participation of SNS in development of resistant hypertension, it should be mentioned that special attention has been paid to the proadrenergic role of sleep apnea syndrome, which has been successfully documented in a number of studies.30–32More direct evidence on the participation of neuroadrenergic factors in the development of a resistant hypertensive state comes from microneurographic data collected by our group in 2 different studies. The first study compared muscle sympathetic nerve traffic values recorded in a group of true resistant hypertensive patients to those found in 35 nonresistant hypertensives and in 19 healthy normotensive controls.33 Second, this variable has been documented in several studies to be elevated in hypertensive patients as compared with healthy controls, paralleling the degree of the neuroadrenergic overdrive.33 Third, a significant correlation between heart rate and cardiac norepinephrine spillover has been found in untreated hypertensive patients.34 Finally, in a number of disease characterized by a marked adrenergic overdrive, such as obesity, metabolic syndrome, heart failure, and hypertension, a significant correlation was detected between resting clinic heart rate and venous plasma norepinephrine or muscle sympathetic nerve traffic.35 Although some exceptions to this general rule may exist,36 there is overall an agreement on the possibility that assessment of clinic heart rate may provide useful insights on the functional status of the SNS in different clinical conditions.In the past decade, attempts have been made to find simple but reliable markers of sympathetic cardiovascular function for being used in daily clinical practice. One of them might be represented by resting clinic heart rate for a number of reasons. First, heart rate has been shown to be an independent marker of cardiovascular risk in a variety of clinical conditions, including essential hypertension.37 The document identifies clinic heart rate greater than 80 beats/minute as the cutoff value above which cardiovascular risk is augmented.37 Of particular interest is the recent finding that heart rate values greater than 80 beats/minute closely mirror an increase in sympathetic cardiovascular drive, as assessed by clinical microneurography  significantly and progressively more elevated from the normotensive to the mild and the more sustained hypertensive state  muscle sympathetic nerve traffic.46 Of special interest is the observation that the procedure when employed in congestive heart failure, i.e., a clinical condition characterized by a massive sympathetic activation,47 may trigger profound sympathoinhibitory effects with a significant improvement in the clinical severity of the disease, as assessed by the New York Heart Association (NYHA) functional class.48The last decade has seen a remarkable interest for considering sympathetic activation at the center of the pathophysiology of essential hypertension and thus as a potential target of the therapeutic intervention. Two procedures in particular have raised the interest of investigators and clinicians, i.e., carotid baroreceptor stimulation and bilateral renal nerves ablation.3 microneurographic investigations produced conflicting results, some studies showing a sympathoinhibitory effect while other no change.49–52 In our own experience, one of the potential problems related to the evaluation of the effects of bilateral renal nerves ablation on SNS refers to the fact that the neurogenic and the blood pressure effects of the procedure do not necessarily share the same temporal pattern of response.53 Indeed in a series of 15 patients with resistant hypertension undergone bilateral renal denervation we examined whether and to what extent the blood pressure responses to the procedure display a pattern qualitatively and quantitatively similar to the one of SNS. To clarify this issue, a serial measurement of clinic and ambulatory blood pressure values, together with sympathetic nerve traffic recording, was performed before and after 2 weeks, 4 weeks, and 6 months from the procedure. Results provide evidence that the sympathoinhibition and the blood pressure lowering effects do not share the same temporal response, characterized by an early reduction in blood pressure and by a late decrease in sympathetic nerve traffic. Taken together these findings suggest that the 2 phenomena are not necessarily linked by a cause–effect relationship and that the blood pressure lowering responses to the procedure in the earlier phase after renal denervation might be mediated by mechanisms other than the SNS ones.Reflecting the controversy generated by the analysis of the heterogeneous blood pressure effects of renal denervation, the results of the procedure on sympathetic nerve traffic, and more in general on sympathetic cardiovascular drive, were also far from being univocal. As mentioned in a previous section of this review, while renal norepinephrine spillover undergoes after renal denervation a substantial reduction,55 Several are the possible factors which may be involved in the phenomenon. These include the poor control of associated cardiovascular risk factors, as shown in many intervention studies, due also to the fact the multifactorial risk profile makes control of the individual risk components much more difficult.37 It may also depend on the genetic profile which makes cardiovascular risk unmodifiable with intervention on blood pressure values. A further mechanism relates to the late initiation of antihypertensive drug treatment, when functional or structural cardiovascular alterations associated with a high blood pressure state become scarcely modifiable by treatment. An additional mechanism, closely related to the sympathetic abnormalities reported in essential hypertension, should be mentioned. Namely the fact that antihypertensive drug treatment, despite its ability to exert sympathoinhibitory effects, does not appear to completely reverse the adrenergic overdrive related to hypertension, leaving the sympathetic function higher than the one seen in the true normotensive individuals.5 This may mean that a not negligible portion of the SNS activation is irreversible and that this phenomenon may adversely affect the cardiovascular risk profile of the treated hypertensive patient.Many studies have shown that despite the favorable effects of antihypertensive drug treatment on cardiovascular morbidity and mortality the cardiovascular risk of treated hypertensive patients remains higher than the one seen in the control normotensive population, even when blood pressure values are reduced to or almost to the recommended blood pressure targets.Data reviewed in this paper document the continuous interest of clinicians and investigators for defining the sympathetic abnormalities characterizing the hypertensive state together with their impact on cardiovascular risk profile, target organ damage, and clinical outcome. Directions for future research in the area include an in-depth analysis of (i) the pathophysiological link between genetic background and the neurogenic abnormalities characterizing hypertension, (ii) the crosstalks between the immune system and the sympathetic neural function, and (iii) the potential impact of antihypertensive combination drug treatment on the neuroadrenergic function, with a specific analysis of what this may mean for the impact of the so-called “residual sympathetic activation” on the residual cardiovascular risk.


A significant association with PCR after logarithm transformation was noted . Retinal measurements  and CVI were not related with PCR. There was a positive association between MAP and PCR after logarithm transformation ; however, chorioretinal factors were not related with MAP. In pregnant women with pre-eclampsia, CT using OCT is a novel factor that is correlated with PCR. Ocular structural alteration in patients with pre-eclampsia may be one of systemic vascular changes caused by pre-eclampsia rather than hypertension.This retrospective study aimed to evaluate the correlation between ophthalmologic factors and proteinuria in patients with pre-eclampsia using swept-source optical coherence tomography (OCT) and OCT angiography. In total, 61 pregnant patients diagnosed with pre-eclampsia were recruited during their hospital stay. The authors investigated the relationship between urine protein–creatinine ratio (PCR) and chorioretinal measurements including choroidal thickness (CT), choroidal vascularity index (CVI), foveal avascular zone (FAZ), vascular density (VD), ganglion cell layer+ (GCL+) and GCL++. The associations between mean arterial pressure (MAP) and ophthalmologic factors were also evaluated. Central subfield CT of the right eye ( Pregnant women undergo adaptive changes in the endocrine, immune and cardiovascular systems to provide an adequate supply for foetus –3. Pre-eThe limitation in penetrance of the previous optical coherence tomography (OCT) hindered in acquiring refined and accurate resolution of the choroid. Recently, the advancement in enhanced depth imaging (EDI) technique or swept-source OCT (SS-OCT) can visualise choroid with higher resolution –13. The Proteinuria is one of the pivotal features of pre-eclampsia. The spot (random) urine protein–creatinine ratio  was considered an alternative, quick and reliable method to assess quantitative proteinuria . The relIn this retrospective study, 61 patients who were diagnosed with pre-eclampsia and referred to the ophthalmology department during the hospitalisation period from July 2017 to May 2020 were enrolled. Patients who were unable to undergo ophthalmologic and obstetrical evaluation and who had any ocular surgery were excluded. This study followed the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of Keimyung University Dongsan Hospital, Daegu, Korea . All data were fully anonymised before we accessed them and the Institutional Review Board waived the requirement for an informed consent.2) was calculated. Multifetal gestation and obstetrical history and previous illness history was investigated. Urine protein, creatinine and albumin concentrations and serum creatinine, albumin, lactate dehydrogenase, aspirate aminotransferase and alanine aminotransferase concentrations were measured. The injection of intravenous magnesium  and use of blood pressure-lowering agents, such as oral nifedipine  and intravenous hydralazine , were investigated. All patients were referred to the ophthalmology department 2 days after admission.Systolic and diastolic blood pressures (BPs) were measured on admission and ophthalmologic examination. Weight and height of the patient on admission were also measured and body mass index .Ophthalmologic examination includes best-corrected visual acuity, intraocular pressure using Goldmann applanation tonometry , refractive error and slit-lamp examination of the anterior and posterior segments. OCT and OCT-A images were obtained using SS-OCT  by one skilled examiner. All OCT scans were performed in the afternoon (12:00 pm to 5:00 pm) to avoid diurnal variations of choroidal status ,19. UsinChoroidal vascularity index (CVI) was calculated to explore vascular regions in the choroid from transfoveal horizontal OCT scans according to the method suggested by Agrawal et al. .In 3.0 × 3.0-mm macular scanning OCT-A, the ‘en face’ images were automatically segmented to the superficial capillary plexus (SCP) and deep capillary plexus (DCP). The area measurement tool equipped in IMAGEnet 6  was used to delineate foveal avascular zone (FAZ); one retinal specialist (JKL) drew a borderline of avascular zone in the superficial and deep retinal vascular images; the area was automatically calculated. The VD  in ETDRS subfields was generated from SCP and DCP images of IMAGEnet 6 using an automated software algorithm. In ETDRS subfields, a 1.0-mm-diameter circle was defined as the central area; the annular area that remained after subtraction of the central area from the 3.0-mm-diameter circle was defined as the paracentral area; paracentral areas were divided into four areas: temporal, nasal, superior and inferior.To evaluate the relationship between ocular measurement and PCR, according to the median value of PCR (1.35 mg/mg), patients were divided into two groups: group 1 (≥1.35 mg/mg) and group 2 (<1.35 mg/mg). The linear relationship with ocular measurement value was explored after converting the PCR, applying logarithm transformation because the PCR values were skewed.p-value < 0.05 was considered statistically significant.SPSS version 20.0 for Windows  was used for performing statistical analysis including independent Student’s t-test and Pearson tests. Measurements from OCT and OCT-A images of the two groups were compared using independent Student’s t-test. The influence of variable factors on choroidal thickness (CT) was examined using Pearson tests. Path analysis was performed using ‘lavaan’ and ‘semPlot’ packages in R3.6.0 (Copyright (C) 2019 The R Foundation for Statistical Computing Platform). A The average age of the 61 enrolled patients was 34.3 years. Intravenous magnesium was injected to 20 patients to prevent epilepsy events. Oral or intravenous blood pressure-lowering agents were administered to 46 patients to control increased blood pressure. Moreover, 31 patients belonged to group 1 and 30 to group 2. Systolic BP and use of intravenous magnesium were significantly high in the group with high PCR .CT in group 1 was statistically greater than that in group 2, except the inferior and central areas in the left eye. VD and FAZ in the superficial and deep retina, CVI, GCL+ and GCL++ showed no difference between the two groups .r = 0.284, p = 0.026) showed significant linear relationship with PCR after logarithm transformation. Other ocular factors failed in demonstrating significant relationship with PCR. The association between CT and CVI was not observed. The mean arterial pressure (MAP) showed significant linear relationship with PCR after logarithm transformation , but there was no significant relationship with other ocular factors r = 0.2842 = 5.193, p = 0.023) and revealed that the model that postulates a direct causal relationship between PCR and CT was valid   .Vascular changes in patients with pre-eclampsia occur systematically. Systemic vasoconstriction is caused by various factors, including the upregulated formation of endothelium and superoxide; decreased formation of vasodilators (such as nitric oxide) and increased vascular sensitivity to angiotensin II. Multiorgan failure follows endothelial dysfunction and hyperpermeability, causing cytotoxic and vasogenic oedema . The choIn patients with pre-eclampsia, vascular endothelial function is damaged, which increases permeability of the glomerular basement membrane against serum proteins and albumins . ProteinCVI is an emerging quantitative biomarker of CT ,30–32. RThere are still some controversies on whether pre-eclampsia affects the retina. In the literature, Kim et al.  and CiloFAZ is an area devoid of retinal capillaries. Recently, the evaluation of clinical correlation and response to treatment via FAZ using OCT-A in diabetic macular oedema and branched retinal vein occlusion has been attempted –40. CiloPathologic fundus findings in patients with pre-eclampsia include optic neuropathy, retinal haemorrhages, Elschnig’s spots, cotton wool spots, segmental or generalised vasoconstriction and serous retinal detachment, which are also commonly found in hypertensive retinopathy . PreviouConsidering these results, we offer two suggestions. First, that chorioretinal pathology and hypertension are independent results of systemic imbalance. Our results showed that hypertension was not related to ocular changes, which conflicts with the previous idea that pathologic ocular findings in pre-eclampsia are induced by hypertension. We may speculate that although systemic imbalance of vascular factors affects both blood pressure and ocular vascular condition, progression to a pathologic occurs independently. Second, we suggest that the previously established model, in which chorioretinal changes in pre-eclampsia are attributed to hypertensive chorioretinopathy, should be replaced with a model that postulates chorioretinal changes primarily arising from pre-eclampsia vascular pathology. Thus, ‘pre-eclampsia chorioretinopathy’ would be a more appropriate term.This study has several limitations. The choroid is an organ sensitive to hormonal situations and gestational age (GA) ,47,48. AIn conclusion, CT in pre-eclampsia is correlated with PCR, implying pre-eclampsia severity. Furthermore, this study makes us reconsider the idea that ocular complications in patients with pre-eclampsia are derived from hypertension but are rather caused by systemic vascular changes in pre-eclampsia.


We studied whether pulse pressure variation (PPV) and stroke volume variation (SVV) can predict fluid responsiveness during thoracoscopic surgery. Forty patients were enrolled in the study. OLV was performed with a tidal volume of 6 mL/kg at a positive end-expiratory pressure of 5 cm H2O, while CO2 was insufflated to the contralateral side at 8 mm Hg. Patients whose stroke volume index (SVI) increased ≥15% after fluid challenge (7 mL/kg) were defined as fluid responders. The predictive ability of PPV and SVV on fluid responsiveness was investigated using the area under the receiver-operator characteristic curve (AUROC), which was also assessed according to the right or left lateral decubitus position considering the intrathoracic location of the right-sided superior vena cava. AUROCs of PPV and SVV for predicting fluid responsiveness were 0.65  and 0.64 , respectively. The AUROCs of indices did not exhibit any statistical significance according to position. Dynamic indices of preload cannot predict fluid responsiveness during one-lung ventilation with CO2 gas insufflation.Thoracic surgery using CO Subsequently, increased intrathoracic pressure in both thoracic cavities may exert a physical influence that can interfere with venous return even under OLV with low tidal volume [2 insufflation at the left thoracic cavity may convey more robust respirophasic variations to the dynamic indices than left-sided OLV. However, no comprehensive evidence yet exists in that regard. Thus, in the present prospective, observational study, we investigated the efficacy of dynamic preload indicators PPV and SVV to predict fluid responsiveness under these circumstances using CO2 insufflation at 8 mm Hg.Pulse pressure variation (PPV) and stroke volume variation (SVV) are widely used dynamic preload indices for fluid therapy and hemodynamic optimization under positive ventilation of general anesthesia . Howevercal view . CO2 gasl volume , while ml volume . In addihttps://cris.nih.go.kr on 28 January 2019 (KCT0003575). After acquiring informed consent from each patient, 40 patients with American Society of Anesthesiologist physical status I, II, or III, aged 20–75 years, who had undergone video-assisted thoracic surgery with CO2 gas between January 2019 and October 2020, were enrolled. Patients with a history of heart failure, cognitive impairment, recent myocardial infarction, and/or stroke (within 3 months of surgery), and diuretic use before surgery were excluded from the study. Patients with heart disease including arrhythmia, left ventricular ejection fraction of less than 45%, and calculated right ventricular systolic pressure of more than 40 mm Hg by echocardiography were also excluded.The current trial was approved by the Institutional Review Board of Yonsei University Wonju College of Medicine, Wonju, Korea, and participants were enlisted at 2), and bispectral index (BIS) were monitored in all patients. Anesthesia was induced by propofol (1.5–2 mg/kg), rocuronium (0.6 mg/kg), and remifentanil (0.03–0.08 mcg/kg/min), and BIS score was maintained between 40 and 60 through the control of remifentanil and desflurane dosage. A radial arterial catheter was placed on the arm of the opposite surgical site and connected to the FloTrac system  and the EV 1000 clinical platform . We continuously monitored stroke volume, stroke volume index (SVI), cardiac output, cardiac index, and SVV through the FloTrac/EV1000 system. PPV was monitored through the Philips IntelliVue MP70 system . Inspired oxygen fractions started with 1.0 in the case of OLV, and decreased to 0.5 in the case of 94% or more pulse oxygen saturation (sPO2). Tidal volume was set at 6 mL/kg of ideal body weight and positive end-expiratory pressure (PEEP) was set at 5 cm H2O. The respiratory rate was adjusted within the range of 10 to 15 breaths per minute and end-tidal partial pressure of CO2 was maintained within the range of between 35 and 40 mm Hg. Peak inspiratory pressure was maintained below 35 cm H2O. When the CO2 gas was injected at 8 mm Hg pressure into the thoracic cage, hemodynamic data were recorded (T1). Subsequently, colloid fluid  was loaded at a rate of 7 mL/kg [All patients fasted from midnight the day before the surgery and received fluids during the fasting period . For premedication, patients received an intramuscular injection of midazolam 1 mg before entering the operating room. In the operating room, ECG, non-invasive blood pressure, pulse oximetry (SpO2 gas inflation.The primary endpoint of the current study was to investigate the predictive power of PPV and SVV for fluid responsiveness (≥15% SVI) during one-lung ventilation with CO2 insufflation.The secondary endpoint of the study was to investigate the predictive power of PPV and SVV for fluid responsiveness (≥15% SVI) according to the site of OLV and COThe null hypothesis was that the area under the curve of the receiver-operating characteristic (AUROC) would be 0.5, and the alternative hypothesis was that it would exceed 0.5. If the expected AUROC is 0.8, α = 0.05, and power = 0.90, 28 patients are needed when the responder and non-responder are assumed to be the same. We included 40 people, considering the potential difference in the ratio of responders and non-responders.t-test, Mann–Whitney U test, or χ2 test as appropriate. Categorical variables were analyzed using chi-square or Fisher’s exact tests. A paired t-test was performed to compare the variables measured at timepoints T1 and T2. The correlation between the SVV at T1 and the percent change of SVI was analyzed using the Pearson correlation coefficient. The ability of these indices to discriminate responders was determined by the AUROCs of SVV and PPV. A p value less than 0.05 was considered statistically significant.All statistical analyses were performed with SPSS 12.0 software  programs. Intergroup comparisons between fluid responders and non-responders were made using an independent 2 gas infusion time between the two groups  0.45–0.82) and 0.65 , respectively. Moreover, subgroup analysis of the AUROC of PPV and SVV on fluid responsiveness according to the RLD or LLD position revealed no significant differences according to the site of OLV and CO2 insufflation, with none of the variables showing any significant predictive ability at any position  was performed with COThe dynamic indices are the observation of the relationship between the difference in stroke volume according to the respiratory cycle during mechanical ventilation and the position in the Frank–Starling curve . PPV and2 insufflation reduces lung and chest wall compliance [Positive insufflation pressure exceeding 5 mm Hg causes the cardiac index, mean arterial pressure, and left ventricular stroke work index to decrease while increasing pulmonary artery and central venous pressure . In addimpliance . Reducedmpliance .2 gas, the AUROC of PPV was 0.65  and 0.64 , respectively, discouraging their use as a preload index. Several factors may have contributed to the inability of these dynamic indices to predict fluid responsiveness during OLV despite maintaining closed chest conditions and positive intrathoracic pressure in both thoracic cavities. First, a low tidal volume (6 mL/kg) is a widely known major factor that may have contributed to predictive failure [2 insufflation at 8 mm Hg while maintaining a closed-chest condition would accentuate the small effect of low tidal volume on the circulatory system and, thus, provide the necessary heart–lung interaction. However, our observation proved otherwise. Second, the amount of non-ventilated lung shunt and hypoxic vasoconstriction may have influenced the dynamic indices regardless of the preload of patients [2 insufflation. In contrast to our hypothesis, the present results are consistent with the conclusion that the dynamic indices do not predict fluid responsiveness in thoracoscopic surgery requiring OLV [In the present study, when the intrathoracic pressure was increased by insufflating 8 mm Hg of CO failure . It was patients . Additiopatients , which mring OLV .2 (RLD position) would provide a more robust respirophasic change in venous return, and thus in preload, than when the surgery is performed on the LLD position. However, both PPV and SVV showed no predictive ability on fluid responsiveness irrespective of the direction of the lateral decubitus position, which may also be attributable to the abovementioned plausible causes.Of note, the current study is unique in that we performed secondary analysis regarding the predictive ability of PPV and SVV depending on the decubitus position. Unlike the inferior vena cava, the SVC is located in the right thoracic cavity and the venous return through the SVC is more influenced by respirophasic changes in the intrathoracic pressure compared to that through the inferior vena cava . Thus, w2 insufflation on PPV, SVV, and SVI would have been informative, but we could not obtain them separately as OLV and CO2 insufflation was performed simultaneously. Finally, the predictive power of the dynamic indices could be affected by the definition of the fluid responders and the amount of fluid challenge. In contrast to previous studies using smaller volumes of fluid challenge, we administered 7mL/kg of fluid while using a ≥15% increase in SVI as a cut-off for fluid responsiveness to ensure sufficient preload augmentation, which would minimize false-negative values.This study has the following limitations. First, only lung protective ventilation, 6 mL/kg of tidal volume, was implemented. Therefore, the effect according to the tidal volume could not be confirmed. There is no accepted guideline of tidal volume in one-lung ventilation, but high tidal volume stretches the lung, which increases the risk of acute lung injury and acute respiratory distress syndrome . As such2 insufflation (8 mm Hg) while maintaining closed-chest condition. Even when accounting for the intra-thoracic location of the SVC, these indices could not predict fluid responsiveness whether the patients were in RLD or LLD position.In conclusion, SVV and PPV could not predict fluid responsiveness in patients undergoing thoracoscopic surgery using one-lung ventilation (6 mL/kg) with CO


Subsequent re-examination candidate trends showed that the rate of nephrologist referrals did not increase. However, the rate of city health guidance referrals significantly increased (p < 0.001). Increase in the re-examination and health guidance examination rates indicate improved awareness of CKD among the public and family doctors, and it is expected to prevent CKD exacerbation in the future.To diagnose chronic kidney disease (CKD) at an early stage, it is important to promote appropriate health guidance and consultation recommendations through regular medical examinations and implementation of continuous high-quality and appropriate treatment. From fiscal year (FY) 2018, Izumo City has initiated the “Izumo City CKD Exacerbation Countermeasures” program. In this study, we aimed to report on the methods undertaken and the effects of this program. Residents aged 40–74 years who underwent specific health checkups from the Izumo City National Health Insurance in FY2018 and FY2019 were included. The rates of CKD re-examination candidates, re-examinations implementation, nephrologist referrals, and health guidance referrals between FY2018 and FY2019 were compared. The rate of CKD re-examination candidates in both years remained unchanged at approximately 7%. The rate of re-examination implementation in FY2019 significantly increased relative to that in FY2018 ( Chronic kidney disease (CKD) in Japan tends to increase annually alongside lifestyle changes and aging; by the end of 2019 ~350,000 patients had been undergoing dialysis ,5: “dissIzumo City is the second most populous city in Shimane Prefecture, with a population of 174,812 inhabitants as at 31 July 2021, and an aging rate of 29.92% for the individuals aged >66 years. There are two nephrology specialized institutions, 11 nephrologists, two diabetes specialized institutions, and 19 diabetologists. The search for countermeasures for diabetic nephropathy exacerbation has been ongoing for some time in the Izumo City; nephrologists have started participating in these efforts and several discussions on how to prevent CKD exacerbation have been held. The “Izumo City CKD Exacerbation Prevention Countermeasures” program using specific health checkups  was init2 (eGFR < 40 mL/min/1.73 m2 for those aged > 70 years); serum creatinine (Cr) > 1.01 mg/dL for males and > 0.9 mg/dL for females, or urinary protein > 2+. The family doctors were instructed to perform a urinalysis  and serum Cr and eGFR re-examinations for patients who brought referral letters. The doctors were requested to refer the patients to a nephrologist if they satisfied any of the following: (1) urinary protein/Cr ratio of > 0.5 g/gCr or urinary protein of > 2+; (2) eGFR of < 50 mL/min/1.73 m2 (eGFR < 40 mL/min/1.73 m2 for those aged > 70 years); or (3) positive for both urinary protein and occult blood   2018  and FY2019  were included in this study. There were 869 individuals who met the re-examination criteria in FY2018 and 906 in FY2019, all of whom were included in the analysis. We sent for “re-examination, specific health checkup (guidance)” , and rece., ≥1+) . Additio2) = 194 × age (year)−0.287 × serum creatinine (mg/dL)−1.094 × 0.739 . The eGFR was calculated at each health checkup facility using a three-variable equation modified for Japanese patients : eGFR , serum Cr, >1.01 mg/dL for males and >0.9 mg/dL for females; and urinary protein, >2+”. Letter of invitation to be sent to a re-examination respondent “who fulfilled the following conditions: estimated glomerular filtration rate (eGFR), <50 mL/min/1.73 mA request form was sent to nephrology specialized institutions when family doctors conducted a re-examination and determined that detailed examinations were necessary. There are five copies: referral source copy, copy from the referral source to Izumo City, copy from the referral source to the nephrologist, copy from the nephrologist to the referral source, and copy from the nephrologist to Izumo City.We compared the rates of CKD re-examination candidates, re-examinations, nephrologist referrals, and city health guidance referrals between FY2018 and FY2019. The survey data in this study were provided by the Izumo City Office in consideration of not identifying personal information.2 test, as appropriate. The number of CKD re-examination candidates, number and rate of re-examinations, and number and rate of nephrologist referrals were analyzed using the χ2 test. Fisher’s exact test was used to analyze the number and rate of city health guidance referrals. Statistical significance was set at p < 0.05. Stata/SE 16.0, StataCorp LLC, College Station, TX, USA) was used for the statistical analysis.The baseline characteristics stratified according to fiscal year were compared using the unpaired t-test, the Wilcoxon rank-sum test, or χThe study protocol was approved by the Ethics Committee of the Shimane University Faculty of Medicine (No. 20210625-3). The requirement for informed consent from all the participants was waived, according to the Japanese Ethical Guidelines for Medical and Health Research Involving Human Subjects. The baseline characteristics of the adults who underwent specific health checkups in FY 2018 were similar to those in FY 2019 . AdditioThe number of patients who underwent specific health checkups in FY2018 was 11,685. Among those, the CKD re-examination candidates were 869 (7.4%). Among the re-examination candidates, 255 underwent re-examinations, 207 did not, and the status was unknown for 407. Among the patients who underwent re-examination, 20 were referred to nephrologists and one underwent health guidance.The number of patients who underwent specific health checkups in FY2019 was 11,315, and 906 (8.0%) of them were CKD re-examination candidates. Among the re-examination candidates, 428 underwent re-examination, 174 did not, and the status was unknown for 304. Among the re-examined patients, 35 were referred to the nephrologists and 31 underwent health guidance.p = 0.105) (The CKD re-examination candidate rate was ~ 7% in both years and showed no significant differences (= 0.105) . p < 0.001) (p < 0.001) (data not shown).Significant differences were observed in the re-examination implementation, non-implementation, and unknown status rates between FY2018 and FY2019, and re-examination implementation rate increased significantly (< 0.001) . Even inp = 0.877)  . p < 0.001)  .To diagnose CKD at an early stage, it is important to promote appropriate health guidance and consultation recommendations such as regular medical examinations and implement continuous high-quality and appropriate treatment. From FY 2018, Izumo City started the “Izumo City CKD Exacerbation Countermeasures” program. In this study, we aimed to report the methods undertaken and the effects of this program.CKD has only a few symptoms, and it is often already advanced by the time symptoms appear. It is difficult to cure exacerbated kidney diseases and may lead to end-stage renal failure and cardiovascular diseases. Therefore, early detection and treatment are important to prevent, exacerbation of the disease. Thus, the “Kidney Disease Countermeasures Study Group” investigated ways to implement kidney disease countermeasures in 2008 and compiled their results in the “Future Kidney Disease Countermeasures” . This reAdditionally, specific health checkups  have beeUrinalysis was initially set as a specific health checkup item, though serum Cr was excluded. However, considering the increase in the number of dialysis patients with diabetes and nephropathy as underlying diseases, serum Cr levels have also been measured at each municipal level.The Japan Kidney Association  was estaCKD countermeasures were initiated throughout Japan, though this was not possible with just medical professionals such as family doctors or nephrologists; it was essential to have the cooperation of government agencies. Some municipalities independently conducted CKD countermeasures; however, many of them conducted those with the aim of preventing the exacerbation of diabetic nephropathy. In Izumo City, the Izumo Area Diabetes Countermeasures Study Group has been conducting activities with the cooperation of the government, Izumo Medical Associations, diabetes specialists, dental associations, and pharmaceutical associations, with nephrologists being involved since 2014. With these efforts, awareness of CKD countermeasures has steadily increased. The “Izumo City CKD Exacerbation Countermeasures” began in 2018.2 (eGFR < 40 mL/min/1.73 m2 for those aged >70 years), serum Cr, >1.01 mg/dL for males and >0.9 mg/dL for females, and urinary protein >2+.” Approximately 7% of those who underwent medical examinations met these criteria in both FY2018 and FY2019. The re-examination implementation rate was 26.8% in FY2018, which significantly increased to 43.9% in FY2019, although this was thought to be due to increased awareness of CKD among the public. Since FY2011, we have launched the Shimane Prefecture Chronic Kidney Disease Countermeasures Council and held events twice a year. On World Kidney Day in March, we gave out handouts to raise public awareness of CKD and conducted health consultations in a commercial department store in Izumo City. Half a year later, in August–September, we hosted a public lecture . We believe that these activities have gradually increased the public awareness of CKD. Furthermore, it is thought that there is an increased enthusiasm toward the dissemination and public awareness of CKD among the government and nephrologists after the launch of the “Izumo City CKD Exacerbation Prevention Countermeasures” program.Based on repeated discussions by study groups, it was decided that re-examinations should be recommended to those who meet the following conditions: “eGFR < 50 mL/min/1.73 mHowever, nephrologist referrals did not increase after the implementation of re-examination. Several possible factors can be considered for this observation. One factor is the possibility that no abnormalities were observed during the re-examination. Patients often refrain from food and water intake the night before undergoing a health examination. This can concentrate the urine and increase the risk of urinary protein positivity; however, improvements were seen as a result of proper water intake at the time of re-examination. Another factor is the possibility that the patients did not wish to visit a university hospital or core hospital, which are nephrology specialized institutions, even if abnormal values were present, since no subjective symptoms were present for CKD. Furthermore, family doctors in Izumo City have long been actively participating in CKD-related lectures, and there is the possibility that they have been able to conduct follow-up examinations to the extent that they can examine patients in their own hospital even after re-examination, with referrals given upon exacerbation. In fact, the number of health guidance referrals in Izumo City has greatly increased; hence, it may be considered that family doctors are actively participating in CKD medical care.The rate of re-examination non-implementation decreased in FY2019; however, the rate of patients undergoing regular observations by family doctors remained unchanged at 70%, and the rate of patients undergoing treatment by nephrologists increased (data not shown). The data in this study could not clarify whether those who were referred to nephrologists in FY2018 were in the process of being treated by nephrologists in FY2019. Furthermore, the number of unexamined patients decreased even when re-examinations were not implemented; hence, it was considered that several patients might have gone to medical institutions in some way and that early detection can be expected in the future.The limitations of this study are that it was a retrospective study and no investigations on changes in renal function or the presence of dialysis were conducted. Future work will require investigations on data collection and tracking methods in collaboration with Izumo City to verify the effectiveness of CKD countermeasures. Moreover, increase in the number of follow-up years would allow further investigation of the changes in eGFR and the development of end-stage kidney disease. Further, although the number cases with unknown status has decreased from FY2018 to FY2019, the proportion still remains high; therefore, this may have affected the results of this program. We are currently working with the Izumo City staff to find a way to reduce the number of cases with unknown status.Additionally, the current referral criteria created by the Ministry of Health, Labor, and Welfare  and the We launched the “Izumo City CKD Exacerbation Prevention Countermeasures” as part of a program for nationwide kidney disease countermeasures. This has not reached the key performance indicator of the Kidney Disease Countermeasures Study Group Report of decreasing the number of patients introduced to dialysis; however, increased re-examination and health guidance examination rates indicating increased awareness of CKD among the public and family doctors were observed. We anticipate further results in the future, and will continue to strive for dissemination and public awareness, improvement of local medical care provision systems, improvement of medical care standards, and human resource development.


Higher baseline glomerular filtration rate (GFR) may yield subsequent steeper GFR decline, especially in patients with diabetes mellitus (DM). However, this correlation in patients with chronic kidney disease (CKD) and the presence or absence of DM remains controversial. We conducted a longitudinal cohort study in a single medical center between 2011 and 2018. Participants with CKD stage 1 to 3A were enrolled and divided into DM groups and non-DM groups, and then followed up at least every 6 months. We used a linear mixed regression model with centering time variable to overcome the problem of mathematical coupling in the analysis of the relation between baseline GFR and the changes, and compared the results from correct and incorrect specifications of the mixed models. A total number of 1002 patients with 285 diabetic and 717 non-diabetic persons was identified. The linear mixed regression model revealed a significantly negative correlation between baseline GFR and subsequent GFR change rate in both diabetic group and non-diabetic group , but no statistical significance in non-diabetic group after within-subject mean centering of time variable . Our study showed that higher baseline GFR was associated with a subsequent steeper GFR decline in the DM group but not in the non-DM group among patients with early-stage CKD. Exact model specifications should be described in detail to prevent from a spurious conclusion. With the progression of CKD, the risk of developing end-stage renal disease (ESRD) increases gradually and so do the cardiovascular complications and deaths5. Traditional risk factors of CKD progression include hypertension, diabetes mellitus (DM), and higher body mass index (BMI)6; however, these factors do not provide a very accurate prediction of the speed of glomerular filtration rate (GFR) decline. Some patients’ GFR show rapid decline, while others remain stable8.Chronic kidney disease (CKD), affecting more than 10% of the people worldwide, becomes a growing public health issue13. The pathophysiology of hyperfiltration in DM comprised several possible mechanisms, such as ultrastructural changes caused by imbalanced release of cytokines and growth factors, and disturbance of vascular tone due to an imbalance of vasoactive humoral factors in response to hyperglycemia15. Moreover, most observational studies and meta-analyses have shown a significant relation between higher baseline GFR and subsequent rapid GFR decline in patients with DM19.Several investigations indicated that higher baseline GFR, such as renal hyperfiltration, may relate to subsequent rapid GFR decline. Higher baseline GFR have been found in early stages of DM if hyperglycemia was not well controlled22. However, there is limited information about the relation between higher baseline GFR and subsequent GFR decline in patients without DM. A recent study showed that higher baseline GFR was significantly related to more rapid decline in GFR over time in patients without DM by using a linear mixed regression model with a random intercept and slope, i.e. the variations in the baseline GFR and in the changes in GFR respectively, to resolve the statistical issue of mathematical coupling17. Mathematical coupling, defined as one variable containing the whole or part of another, could yield a spurious correlations between two variables irrespective of any true association, thereby leading to questionable conclusions25. Although linear mixed model can tackle the issue of mathematical coupling, correct specification of the random effects is essential for yielding a meaningful interpretation of the correlation between the random intercept and slope26. However, previous studies did not always describe their model specifications in detail, and it is, therefore, unclear whether the issue of mathematical coupling has indeed been resolved.The phenomenon of higher baseline GFR was also found in people with intolerant fasting glucose, obesity, pregnancy, or high protein dietTo investigate the relationship between the baseline GFR and subsequent GFR change, we used an early stages of CKD cohort comprising patients with DM and without DM. We used linear mixed model to overcome the mathematical coupling in the analysis of the relation between the baseline GFR and its changes. We also compared results from correct and incorrect specifications of mixed models to assess the impact of mathematical coupling. We hypothesized that higher baseline GFR is a risk factor of a rapid GFR decline in patients with DM but not in those without DM.2 < GFR < 60 ml/min/1.73 m2 or GFR ≥ 60 ml/min/1.73 m2 with a urinary protein-to-creatinine ratio (UPCR) ≥ 150 mg/g or significant findings of renal pathology for at least 3 months28. Patients, who had acute kidney injury within three months, Child Pugh class B to C liver cirrhosis, or terminal malignancies, were excluded. We then divided the cohort into DM (including type 1 and type 2 DM) and non-DM groups to proceed with statistical analyses. This study has been approved by the Research Ethics Committee of the National Taiwan University Hospital (202006020RINB). As this study was retrospective and observational, participants written informed consent was waived by the Research Ethics Committee of the National Taiwan University Hospital.This study is a retrospective analysis of data from a single medical center, National Taiwan University Hospital. Patients, who agreed to participate the early CKD program between 2011 and 2018, were included, if their ages were between 18 and 80 years and were diagnosed with chronic kidney disease stage 1 to 3A, which was defined as a 45 ml/min/1.73 m29. The high-risk population of CKD progression includes people of being older than 65 years old, family history of CKD, diabetes mellitus, and hypertension.The early CKD program was initiated by the National Health Insurance Bureau, the Ministry of Health and Welfare in Taiwan, to care patients with CKD stages 1 to 3a in high-risk population since 20112 or UPCR≧1000 mg/gm, they were transferred to the Pre-ESRD program for further management29.These patients were invited to join this program on their visits to outpatient clinics. A comprehensive educational program, consisting of basic knowledge of chronic kidney disease, risk factors, lifestyle modification and medical treatment, was provided. The participants returned to the clinic every 3–6 months, according to the clinical presentations of patients and judgments of primary care physicians. They attended classes of the educational programs and undertook routine laboratory tests at least every 6 months. Once patients’ GFR was lower than 45 ml/min/1.73 m−1.154 × Age −0.203 × 0.742 ) 0.912] , which was developed by using linear regression of the difference on the average of log-transformed inulin clearance and the MDRD, CKD-Epidemiology Collaboration (CKD-EPI) equations, and has been validated and shown to be more accurate and precise than MDRD-4 variables and CKD-EPI equations for Taiwanese adults30.Basic personal information of age, sex and underlying comorbidity were recorded. Body height, weight, blood pressure and biochemical data, including serum creatinine, low-density lipoprotein cholesterol, fasting glucose and HbA1c (only for DM patients) and UPCR were recorded at baseline and every 3 to 6 months. The estimated GFR (eGFR) was calculated by the Taiwanese MDRD equation [1.309 × (186 × (serum creatinine)26. The basic linear mixed model is written as:jth patient on ith occasion; jth patient Time is the centered time variable, i.e. the centered duration of observation in years for each patient; jth patient r between the baseline eGFR and the subsequent changes in eGFR by using the formulae: 2) and succeeding eGFR changes (ml/min/1.73 m2 per year) was evaluated by the correlation between the random intercept and slopes. We also conducted the same analyses without centering the time variables to assess the impact of mathematical coupling on the estimation of the correlation between the baseline eGFR and the change. We performed covariates adjustment, including sex and age in model 1, then plus BMI and systolic blood pressure (SBP) in model 2, and added current smoking status, HbA1c (only in diabetes mellitus group) and urine protein-creatinine ratio in model 3. A P-value < 0.05 was considered statistically significance. The statistical software Stata version 14  (https://www.stata.com/) was used for data analysis. All methods carried out were in accordance with relevant guidelines and national legal regulations.We used the mean ± standard deviation (SD) to summarize continuous variables, and relative frequency for categorical variables. The differences between the two groups were analyzed by using the t-test or the chi-squared test. Variables with a non-normal distribution were analyzed by the Mann–Whitney U test. A two-level linear mixed regression model with the random intercept and slope was used to analyze eGFR measurements and solving the statistical problems of mathematical coupling. The dependent variable was the absolute value of eGFR. The time variable was the duration of observation starting from the date of the first visit up to that of the last visit in nephrology outpatient department. To test the appropriate null hypothesis in multivariable linear mixed regression model, we undertook within-subject mean centering for the duration of observation to correct for the effects of mathematical coupling between random intercept and slope2, p < 0.001, respectively). Mean baseline eGFR was 58.5 ± 18.1 (SD) ml/min/1.73 m2 in the non-DM group and 57.4 ± 16.3 (SD) ml/min/1.73 m2 in DM group by the Taiwanese MDRD equation. The eGFR declined gradually in both DM and non-DM groups  showed that males and older age had a significantly negative association with baseline eGFR; the average baseline eGFR of men was 4.61 ml/min/1.73 m showed tIn the DM group, a significantly consistent negative correlation between GFR at baseline (random intercept) and GFR change rate (random slope) was found after multivariable adjustment . After within-subject mean centering for the time variable, the correlations decreased substantially  . However, after within-subject mean centering for the time variable, the negative correlation between GFR at baseline and GFR change became much smaller and no longer statistically significant   and higher systolic pressure were associated with a significantly smaller decrease in eGFR. Naïve analyses without centering of the time variable found a significantly negative correlation between GFR at baseline and GFR change in DM and non-DM patients with CKD. After within-subject mean centering, a significant but moderate correlation were observed only in DM patients with CKD. This indicates the impact of mathematical coupling on the estimation of the correlation between GFR at baseline and GFR change cannot be overlooked, and this is consistent with findings in the previous methodological studies36. Moreover, Melsom et al. showed that this significant correlation existed not only in patients with DM but also in those without DM17. In contrast, no substantial correlation between baseline GFR and subsequent GFR decline was also found in other investigations38. This inconsistency may be attributed to considerable GFR variations over time, such as age-related GFR decline, GFR measurements, and inappropriate statistical methods for assessing the relation between GFR at baseline and its changes40. In our study, a negative relation between the baseline eGFR and subsequent decline was found only in patients with DM but not in patients without DM.It is still controversial whether hyperfiltration with higher baseline GFR is related to subsequent GFR decline. Some studies revealed that hyperfiltration with higher eGFR was associated with more rapid eGFR decline in patients with type 1 or type 2 DM41. However, the estimated GFR was more readily available and cost-effective in the clinical practice than GFR via direct measurement, which was difficult to replicate due to different physiological conditions and great variations over time. Two of the most common equations for estimating GFR were MDRD-4 variables and CKD-EPI worldwide. However, the MDRD-4 equation was created by using data from Caucasians and African Americans with CKD and is likely to underestimate GFR, when eGFR greater than 60 mL/min/ 1.73 m243. The KDIGO 2012 guidelines recommend using the CKD-EPI equation in adults, unless an alternative equation has been shown to be more accurate in the specific population44. In our study, we used a corrected MDRD equation (Taiwanese MDRD), because it has been shown to have better precision and a lower bias than the equations of the MDRD-4 and CKD-EPI in Taiwanese population30.The accurate measurement of GFR should examine the clearance of materials which are only through renal filtration, such as iohexol, iothalamate, inulin, etc.25. Some studies applied a linear mixed regression model with random intercept and slope to resolve this statistical issue and to attain correct results17. However, the correct null hypothesis for testing the correlation between the baseline value and subsequent change is not zero, because these two variables have an underlying mathematical relation by sharing a common component of the baseline value25. It has been shown that centering the time variable could overcome this underlying mathematical relation and then attain an accurate result of null hypothesis test45. In this study, we undertook within-subject mean centering for the time variable to investigate the relationship between the baseline eGFR and its changes. We observed that the negative correlations are always attenuated after centering when compared with those given by the conventional approach without centering, in DM and non-DM patients with CKD. Moreover, in non-DM patients, this negative correlations were no longer statistically significant, after correct methodologies were used. This implied that higher baseline eGFR or renal hyperfiltration may be only a subclinical indicator but not the major cause of renal damage in patients with DM and early-stage CKD. Furthermore, when patients’ GFR was lower than 45 ml/min/1.73 m2, they would be transferred to the Pre-ESRD program, and their eGFR values were no longer being included in our analysis. This may lead to the truncation of low eGFR values, resulting in the reduction in the variances of follow-up eGFR and the over-estimation of the negative relation between the baseline eGFR and its changes. Our study suggests that previous evidence on the relation between the baseline eGFR and the decline in eGFR should be interpreted with great cautions and may require reevaluation.Analysis of the relation between the baseline and changes suffered from mathematical coupling, which gives rise to misleading results and invalid testing of the null hypothesis46. These data showed a similar distribution to our study. Therefore, it needs to be cautious to apply findings in our study to other populations with different sex proportions or age distributions. Third, the mean eGFR in our study was lower than the traditional definition of hyperfiltration with high GFR. The focus of our study is not the consequence of renal hyperfiltration but proper analyses of the relation between higher baseline GFR and subsequent GFR change. Moreover, the number of nephrons varied among individuals and usually decreased with age or renal injury39. Glomerular hyperfiltration or single-nephron hyperfiltration in people with fewer numbers of nephrons may show a normal or mildly low level of whole-kidney GFR, which is equal to single-nephron GFR multiplied by nephron numbers47. Therefore, results from our study still provides evidence on the relation between higher eGFR and subsequent eGFR changes. Finally, patients with GFR lower than 45 ml/min/1.73 m2 or UPCR≧1000 mg/gm were transferred to the Pre-ESRD program for further management. Therefore, informative censoring may be a concern, since the information from those with rapidly deteriorating kidney function were selectively missing. This may be regarded as a problem with the truncated data, since GFR lower than a threshold was unavailable. This is likely to lead to a decrease in the variance of GFR with the increase in follow-up of the cohort, yielding a spurious, negative correlation between the baseline GFR and changes in GFR25. Therefore, the negative correlation between GFR at baseline and GFR changes in patients with CKD and DM may be weaker than what has been observed.Our study has some limitations. First, we included a relatively small number of participants, especially in patients with DM. Despite this problem, our study collected sufficient data of repeated measurements during the long-term follow-up to achieve robust inference. Second, our study included a higher proportion of men and elderly in DM and non-DM groups. According to previous national study, near two thirds of adults with CKD was more than 60 years old (63.3%), and men had a higher prevalence of early-stage CKD than did women (11.7% versus 9.9%)In conclusions, a significantly negative correlation between GFR at baseline and GFR changes was found in patients with CKD and DM, but no such correlation was found in non-DM patients with CKD when correct statistical analyses were undertaken. Higher baseline eGFR or renal hyperfiltration may be only a subclinical indicator but not the major cause of renal damage in patients with DM and early stage CKD. Our findings suggest that higher baseline GFR was associated with a greater GFR decline in DM patients but not in non-DM patients. Investigations about baseline value to subsequent changes should describe model specifications in detail to assure resolving mathematical coupling and then prevent from a spurious conclusion.