Chronic kidney disease (CKD) is a significant comorbidity in patients with heart failure and valvular heart disease. Renal impairment is not well evaluated in the patients with Stage B progressive aortic regurgitation (AR) (mild to moderate and moderate grades in this study), for estimating outcome.We sought to investigate the prognostic factor, especially CKD, in the patients with progressive AR.n = 70) and non‐CKD (n = 192) groups, which CKD was defined as estimated glomerular filtration rate < 60 ml/min/1.73 m2. The primary outcome was major adverse cardiac events (MACEs), including cardiac death, myocardial infarction, hospitalization for heart failure, and aortic valve replacement.We enrolled 262 patients with Stage B progressive AR and preserved left ventricular systolic function (ejection fraction ≥ 50%). Based on the presence of CKD, the patients were divided into CKD , higher right ventricular systolic pressure . The CKD group was associated with increased risk of MACEs . In multivariate Cox regression analyses, the risk of MACEs was significantly different between groups ; furthermore, the risk of hospitalization for heart failure  was significantly higher in the CKD group than in the non‐CKD group.The median follow‐up duration was 41.5 (interquartile range: 16.2–71.7) months. Between groups, the CKD patients were older; they had a higher pulse pressure and higher incidence of hypertension, diabetes mellitus, dyslipidemia, cerebrovascular accident, and atrial fibrillation. Compared to the non‐CKD group, the CKD group had lower In patients with Stage B progressive AR, CKD is an independent prognostic factor for clinical outcomes . Chronic kidney disease is a known comorbidity for valvular heart disease.We investigated that chronic kidney disease was an independent prognostic factor for clinical outcomes  in patients with Stage B progressive aortic regurgitation.Although Stage B progressive aortic regurgitation should be carefully monitored in all patients by guideline, special attention should be paid to patients with pre‐existing chronic kidney disease. The natural history of AR is well defined; it has a gradually progressive clinical course with effects on the left ventricle, including eccentric hypertrophy, fibrosis, and ultimately, cardiac failure.Approximately 6% of the patients with AR develop symptoms of left ventricular (LV) systolic dysfunction each year; moreover, the mortality rate is about 10% per year in the presence of LV systolic dysfunction.Chronic kidney disease (CKD) is a significant comorbidity for most major cardiovascular diseasesThere is not much clinical evidence on the prognostic factors for Stage B progressive AR, and little information is available on the effects of CKD in these patients. This study aimed to evaluate the prognostic factors, especially the impact of CKD, in patients with Stage B progressive AR.22.1In this retrospective cohort study, we retrieved data of patients with a mild to moderate or higher grade of valvular heart disease from the echocardiographic registry of our institution, between 2010 and 2019.n = 645) and reviewed their medical records. Next, we selected patients with a medical record of follow‐up and excluded those with the following conditions: severe grade of AR (Stages C and D)First, we searched the registry to identify patients with AR  were collected between 1 month before and after the echocardiography was performed. For eGFR values, the Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) equation was used.We divided our study cohort into two groups based on their renal function: the CKD group and the non‐CKD group. The CKD was defined as estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73 m2.2E velocity) was measured using the pulsed‐wave Doppler method by placing the sample volume at the tip of the leaflets of the mitral valve. Tissue Doppler‐derived early‐diastolic mitral annular velocity (eʹ velocity) was measured at the septal corner of the mitral annulus in the apical four‐chamber view. In addition, deceleration time was measured for the early transmitral flow velocity. E/eʹ ratio was used to estimate the LV filling pressure.Commercially available ultrasound equipment was used for echocardiographic studies. Conventional two‐dimensional echocardiography was performed, and echocardiographic parameters were obtained following the American Society of Echocardiography guidelines. LV end‐diastolic and end‐systolic volumes were measured using apical two‐ and four‐chamber views, and the ejection fraction was calculated using Simpson's rule.For assessment of AR severity, an integrated echocardiography examination, including visual parameters, the AR jet width at the aortic valve, the jet height in the LV outflow tract, the strength of the AR continuous wave signal, and the pressure half time, was performed. The presence of pan‐diastolic flow reversal in the proximal descending aorta was considered to indicate severe AR.2.3The date of the patient's baseline echocardiography was considered the beginning of the observation period. All enrolled patients were followed up via a chart review, and the date of last follow‐up or death was recorded. The patients, whose end point was unknown, were treated as follow‐up loss patients using statistics. All outcome events were adjudicated by investigators.The primary outcome was a composite clinical outcome—major adverse cardiac events (MACEs), including cardiac death, myocardial infarction, hospitalization for heart failure, and aortic valve replacement. The secondary outcome was hospitalization for heart failure.2.4t‐test and presented as the mean with standard deviation or median with interquartile range (IQR). Categorical data were tested using Fisher's exact test or χ2 test, as considered appropriate.Continuous variables were compared using Student's p < .20 or clinically meaningful parameters were then entered into a multivariate Cox regression model. Demographic parameters such as age and sex were necessarily included in clinically meaningful parameters, and hypertension (HTN), diabetes mellitus (DM), and dyslipidemia were also applicable in these. Eventually, adjusted HRs were compared using multivariate Cox proportional hazards stepwise regression model based on age, sex, pulse pressure, HTN, DM, hyperlipidemia, cerebrovascular accident, atrial fibrillation, and eʹ velocity.Independent prognostic factors for clinical outcomes were analyzed using Cox proportional hazards regression models. Results were presented as hazard ratios (HRs) with corresponding 95% confidence intervals (CIs). Variables from univariate analyses with In addition, a Kaplan–Meier analysis was used to describe the event‐free survival, and the log‐rank test was used to analyze the differences between the groups with and without CKD.p < .05 were considered statistically significant. All statistical analyses were performed using Statistical Package for the Social Sciences .All tests were two‐tailed, and values of 33.1n = 70) and non‐CKD (n = 192). Table Our final cohort consisted of 262 patients, divided into two groups: CKD (‐CKD n = 92. Tablep < .001). NT‐proBNP level in blood is affected by creatinine level, that is, renal function. Since the two groups were divided according to the presence or absence of CKD, we considered that the NT‐proBNP level was inevitably statistically different between two groups.In addition, the CKD group showed higher levels of N‐terminal probrain natriuretic peptide (NT‐proBNP) than the non‐CKD group  was significantly higher in patients without CKD.The 3.3Table p = .017). The risk of MACEs in the CKD group was significantly different  on multivariate analysis using Cox regression model adjusted for age, sex, pulse pressure, HTN, DM, hyperlipidemia, cerebrovascular accident, atrial fibrillation, and eʹ velocity.Cox regression analysis revealed significant differences between the two groups in the rate of the primary outcome . Additionally, the risk of cardiac death was also significantly higher in the CKD group . However, there were no significant results in myocardial infarction and aortic valve replacement.Likewise, the risk of hospitalization for heart failure was significantly higher in the CKD group than in the non‐CKD group after adjustment  the patients in the CKD group were significantly older and had higher pulse pressure and higher incidence of HTN, DM, dyslipidemia, cerebrovascular accident, and atrial fibrillation; (2) on multivariate Cox regression analyses, the risk of clinical outcomes  was significantly higher in the CKD group than in the non‐CKD group.eʹ velocity were the statistically significant variables. And, in the multivariate analysis about risk of heart failure for hospitalization, CKD and pulse pressure were the statistically significant variables. In the study to identify prognostic factors, CKD, which proved statistical significance in predicting both composite clinical outcome and heart failure, would be the main result in this study.In the multivariate analysis about the risk of MACEs, CKD, hyperlipidemia, and Because of progressive dilatation and hypertrophy, the ventricle can maintain a normal stroke volume despite elevated afterload in the early phase of AR. In the literature, the mechanism underlying AR progression is explained as an increase in end‐systolic dimensions and ventricular wall stress leading to a gradual decline in LV function, resulting in the development of symptoms. Nevertheless, there are only a few published studies that have described the prognosis of mild and moderate AR.Severe deterioration of LV function usually occurs insidiously, and the LV function may improve after correction of regurgitation.Patients with CKD suffer from a high burden of cardiovascular disease with increased cardiovascular mortality, an accelerated progression of atherosclerosis and valvular heart disease, an increased risk of congestive heart failure, and an increased risk of sudden cardiac death.In the literature, there are various findings on the impact of advanced CKD on aortic valve hemodynamics.A shift in the age distribution of a population toward elderly individuals in the coming decades may further amplify the burden of AR on the healthcare system. Our results provide supporting evidence for developing echocardiography surveillance strategies endorsed by current guidelines and may assist in defining clinical recommendations for managing patients with Stage B progressive AR. Furthermore, given the prognostic role of CKD, the study results may help identify patients with increased risk of AR progression or excess risk of mortality requiring tailored therapy.This study was a retrospective study, and all data were recorded in a single clinical database. We reported composite clinical outcomes.Instead of a quantitative assessment, including regurgitant volume and regurgitant orifice area, an integrated echocardiographic assessment, with the final adjudication by a cardiac physiologist, was used to evaluate AR. We tried to evaluate the clinical outcome at a progressive stage rather than quantitative AR evaluation. Eventually, this could be a sufficient and well‐established methodology, as comprehensive quantitative assessment may not be feasible in all patients.5In the long term, impaired renal function negatively impacts the clinical outcomes  in patients with Stage B progressive AR. Although Stage B progressive AR should be carefully monitored in all patients, special attention should be paid to patients with pre‐existing CKD. Dedicated management efforts should be undertaken to optimize clinical adverse event (such as heart failure) prevention in these patients.The authors declare that there are no conflict of interests.


Hypertension and chronic kidney disease are closely linked. Patients with chronic kidney disease have hypertension almost universally and uncontrolled hypertension accelerates the decline in kidney function. The pathophysiology of hypertension in chronic kidney disease is complex, but is largely related to reduced nephron mass, sympathetic nervous system overactivation, involvement of the renin-angiotensin-aldosterone system, and generalized endothelial dysfunction. Consensus guidelines for blood pressure targets have adopted a blood pressure <120/80 mm Hg in native chronic kidney disease and <130/80 mm Hg in kidney transplant recipients. Guidelines also strongly advocate for renin-angiotensin-aldosterone system blockade as the first-line therapy. Moreover, uncontrolled hypertension has a graded relationship with cardiovascular disease and remains a leading cause of cardiac morbidity and mortality. In this article, we review the classification of blood pressure (BP), goals of BP reduction, and hypertension management in those with CKD.Hypertension is a common finding in individuals with chronic kidney disease (CKD), afflicting 65% to 85% of patients and increasing as kidney function declines.2 With the change in hypertension diagnosis thresholds in the 2017 American Heart Association/American College of Cardiology (AHA/ACC) guidelines, an OBP < 120/80 mm Hg is still considered normal, but an OBP of 120–129/ <80 mm Hg is elevated, and an OBP ≥ 130/80 mm Hg is consistent with hypertension.2 An OBP reading of 130/80 mm Hg is thought to correlate with a 24-hour average reading of 125/75 mm Hg, and the recommended 24-hour ABPM targets are: 24-hour mean BP ≤ 125/75 mm Hg, a daytime BP ≤ 130/80 mm Hg, and a nighttime BP ≤ 110/65 mm Hg with appropriate nocturnal dipping.2 When both OBP and ABPM are available, individuals may be classified into one of four groups: controlled , white coat hypertension , masked hypertension , and sustained hypertension (elevated office and ABPM).An office blood pressure (OBP) of 140/90 mm Hg is thought to correlate with a 24-hour average ambulatory blood pressure measurement (ABPM) of 130/80 mm Hg and a mean home BP of 135/85 mm Hg.3 In the Chronic Renal Insufficiency Cohort (CRIC) study, 1,502 participants with CKD had ABPM profiles available for review. Masked hypertension was associated with more cardiovascular events and a more rapid decline in kidney function after a mean follow-up of 6.72 years.4 Increasing use of ABPM or home blood pressure monitoring (HBPM) in clinical CKD practice will help confirm treatment responses and perhaps better characterize risk for future target organ damage.Masked hypertension (30–60%) in CKD has a higher prevalence compared to the general population (10–25%).5 Standardized OBP measurements should include: (1) appropriate cuff size (bladder should encircle 80% of the bare arm); (2) proper positioning ; (3) patient preparation  multiple measurements (≥ 2 readings at least 1–2 minutes apart) in both arms while using a validated device that is appropriately calibrated.5 Importantly, these measurements should be done without the white coat provider being in the room.Routine in-office BP measurements served as the traditional method for hypertension diagnosis and treatment decisions until recent recommendations favored implementation of standardized practices.8 Agarwal et al. compared routine versus standardized BP measurements in 275 participants from the Systolic Blood Pressure Intervention Trial (SPRINT). The mean systolic blood pressure (SBP) and diastolic blood pressures (DBP) in routine office measurements were 12.7 and 12 mm Hg higher, respectively, than the standardized measurements performed on the same day.8 Moreover, studies have implicated poor proficiency by medical staff in following standardized BP measurement protocols, therefore re-training should occur on a regular basis.11Many studies have demonstrated the lack of correlation between routine and standardized OBP measurements.12 ABPM provides a more robust estimate of the 24-hour, daytime and nighttime readings, including BP variables such as dipping and BP decline > 10% during sleep. Both nocturnal hypertension and non-dipping status are prevalent in CKD and are associated with higher risk of cardiovascular morbidity and mortality.13Out-of-office BP measurements should complement standardized OBP measurements and include both ABPM and HBPM. Briefly, ABPM involves the application of an appropriately sized BP cuff to the nondominant arm with BP measurements taken every 20 to 30 minutes for a 24- to 48-hour period. While following their normal daily routine, individuals are instructed to keep their arm still during measurements and to keep a diary of sleep and wake periods.14 In September 2015, the randomized SPRINT trial stopped before completion—after the interim analysis showed the group assigned to an intensive systolic BP goal < 120 mm Hg had a 25% lower cardiovascular disease risk and 27% lower all-cause mortality compared with the standard group assigned to systolic BP < 140 mm Hg.15 Subsequent guidelines from the AHA/ACC in 2017 recommended a BP goal of <130/80 mm Hg in patients with CKD and those with increased cardiovascular risk. The AHA/ACC chose 130 mm Hg instead of BP < 120 mm Hg due to concerns that routine clinic visit BP measurements are unlikely to be measured in a standardized approach such as that used in the SPRINT trial.16 In addition, there were more hypotensive and acute kidney injury events requiring emergency department visits among participants in the intensive group. Citing these concerns, the 2018 European Society of Hypertension and European Society of Cardiology (ESH/ESC) guidelines recommended a goal of SBP between 130 and 139 mm Hg in CKD hypertension.17The optimal BP targets for CKD hypertension treatment have evolved as new research accumulates .14 In Se5 This recommendation followed subgroup analysis that tested the two BP targets (SBP < 120 vs SBP < 140 mm Hg) among 2,600 CKD patients in SPRINT and showed lower composite cardiovascular outcome  and lower mortality  after median follow-up of 3.3 years in the intensive arm.18 Fortunately, kidney outcomes such as the development of end-stage kidney disease (ESKD) or a greater than 50% reduction in estimated glomerular filtration rate (eGFR) were not more pronounced between the two groups, with one exception: a more pronounced eGFR decline in the intensive group in the first 6 months , attributed to an acute hemodynamically mediated decline in the renal blood flow, without further appreciable change over the remainder of the study.18Newer recommendations from the 2021 Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guidelines have favored more intensive treatment to a SBP of < 120 mm Hg.21 These studies had few cardiovascular and mortality events, making data synthesis challenging for evidence-based practice guidelines. A meta-analysis performed by Malhotra et al. later examined mortality among CKD subgroups, including these three trials, and showed a lower mortality in the intensive BP control group .22 However, intensive BP targets among all four studies showed no benefit for reducing kidney outcomes.23 Taken together, an intensive BP target seems appropriate for reductions in cardiovascular complications, particularly given the higher cardiovascular risk in people with CKD.The SPRINT trial differed from three previous trials comparing BP targets in CKD due to heterogeneity in primary outcomes. The Modification of Diet in Renal Disease (MDRD) trial, the African American Study of Kidney Disease and Hypertension (AASK) trial, and the Blood-Pressure Control for Renoprotection in Patients with Non-diabetic Chronic Renal Disease (REIN-2) trial used kidney outcomes (ESKD and reduced eGFR) as primary outcomes instead of cardiovascular outcomes.25 Individuals with WCH have uncontrolled clinic blood pressures but normal out-of-office blood pressures and represent up to 30% of clinically uncontrolled hypertensive CKD patients. The diagnostic failure of these two phenotypes have led to under- and overtreatment, respectively.12 Ku et al. showed the clinical relevance of these conditions among 610 participants in the AASK trial, which revealed a U-shaped association between clinic and ambulatory SBP difference and an increased mortality but no ESKD risk.26 However, the generalizability of this trial to all hypertensive CKD patients is unknown. The ongoing 4-year prospective randomized MASked-unconTrolled hypERtension management based on office BP or on ambulatory blood pressure measurement (MASTER) study may help clarify this ambiguity if it indicates that ABPM-based treatment strategies slow target organ damage and reduce future CV events.27The 24-hour ABPM can help ensure BP targets are met by identifying two specific BP phenotypes in hypertensive CKD patients: masked uncontrolled hypertension (MUCH) and white coat hypertension (WCH). MUCH, defined as normal clinic blood pressures but uncontrolled out-of-office blood pressures, is grossly underrecognized. Up to 60% of clinically normotensive CKD patients are uncontrolled out of the office and possibly face increased cardiovascular (CV) risk and accelerated kidney function decline.28 Reducing sodium intake to less than 2 grams daily may lower SBP by 5 to 10 mm Hg, and increasing potassium intake to more than 3 grams daily may be additive in those who are salt sensitive.29 However, dietary sodium reduction should not be a universal recommendation as it will have little impact on BP in those with CKD and salt-losing nephropathies.30 More importantly, high potassium content of many of these BP-friendly foods may even provoke hyperkalemia.Dietary interventions and daily exercise are adjuncts to pharmacologic therapies and should be the first step to hypertension management. The Dietary Approaches to Stop Hypertension (DASH) diet, which favors fruits and vegetables over saturated fats, has led to modest BP declines in hypertensive individuals.32 This effect on eGFR, however, was inconsistent in newer studies.36 To align guidelines, KDIGO and AHA/ACC now recommend “a total duration of 150 minutes of moderate intensity physical activity (resistance or aerobic) per week.”37 Individuals with CKD that have limited exercise ability due to their comorbidities should perhaps have this exercise target modified accordingly. Weight loss of more than 5 kg can enhance the favorable exercise benefits by lowering the SBP by 5 mm Hg.38 For those with obstructive sleep apnea, a recent meta-analysis showed nocturnal continuous positive airway pressure treatment can have a modest reduction in SBP by up to 5 mm Hg in the most severe cases.39 This is highly relevant as sleep disturbances and sleep apnea are extremely common in CKD.40Regular exercise should be encouraged to help lower blood pressure and improve CV health in CKD, not to mention its beneficial effects on quality of life. Prior studies suggest that exercise implementation may improve eGFR at 12 months or slow CKD progression.2 Little to no evidence is available on outcomes comparing different drug combinations in CKD. The typical primary agents are renin-angiotensin-system inhibitors (RAAS), which include angiotensin-converting enzyme inhibitors (ACEi), and angiotensin receptor blockers (ARB), as well as calcium channel blockers (CCB) and diuretics. Beta blockers, on the other hand, lack evidence of benefit, increase risk of new-onset type 2 diabetes, and perhaps should be avoided as first-line therapy unless indicated for cardiovascular disease.42Antihypertensive medications are almost always needed in patients with CKD. When initiating antihypertensive medication, one should consider starting two drugs from different classes, particularly in those with Stage 2 hypertension (≥ 140/90 mm Hg).43 Ruggenenti et al. showed ramipril’s salutary effect in slowing eGFR decline among 166 proteinuric patients (> 3 g/d) compared with placebo  in the Gruppo Italiano di Studi Epidemiologici in Nefologia (GISEN) study, or Ramipril Efficacy In Nephropathy (REIN) follow-up study.44 A meta-analysis of 119 randomized controlled trials showed ACEi and ARBs reduced kidney failure by 39% and 30%, and reduced major cardiovascular events by 18% and 24%, respectively, versus placebo.45 The combination of ACEi and ARBs is discouraged because it is associated with higher rates of acute kidney injury (AKI) and hyperkalemia.46 In the ESKD population, dosing adjustment should be considered in those without residual kidney function. For example, lisinopril dosing should be three times weekly instead of daily, preferably after hemodialysis due to potential for being removed with dialysis.47ACEi and ARBs are the mainstays of CKD hypertension management, particularly in those with albuminuria .48 There is also evidence to suggest nondihyropyridine CCBs  have a more pronounced antiproteinuric effect and may be a reasonable therapeutic option for proteinuric CKD despite maximal doses of ACEi or ARBs.49 CCBs such as nifedipine should be avoided particularly in those with proteinuria as they may transmit systemic pressures to the glomerular space more readily.There is less consensus concerning the optimal second-line antihypertensives. Dihydropyridine calcium channel blockers, such as amlodipine, are commonly used as an adjunct to an ACEi or ARB on the basis of their synergistic ability to reduce BP.2.50 However, the evidence against thiazide use in advanced CKD is weak. A recent randomized control trial showed that, for patients with stage 4 CKD, the addition of chlorthalidone to traditional antihypertensives reduced SBP by 11 mm Hg  at 12 weeks.51 Chlorthalidone and indapamide are preferred over hydrochlorothiazide due to their longer half-lives and higher potency, and reductions in GFR may be met with increased drug dosages.52Diuretics are also a reasonable second-line therapy choice, especially in those with reduced kidney function and hypervolemia. The prevailing dogma has been that thiazide diuretics lose effectiveness at a lower GFR, and guidelines have recommended changing from a thiazide to a loop diuretic at GFR values below 30 mL/min/1.73 m53 Prior to diagnosing an individual with resistant hypertension, clinicians should confirm accurate clinic BP measurements as well as use out-of-office BP measurements to exclude pseudo-resistance. Mineralocorticoid receptor antagonists (MRA) such as spironolactone and eplerenone have been found to reduce BP in resistant hypertension.54 However, hyperkalemia may be a concern, particularly when added to a background of ACEi or ARBs in the setting of reduced GFR, as seen with advanced CKD. AMBER trial results showed that use of the oral potassium binder patiromer enabled more patients with resistant hypertension and CKD to continue spironolactone.55 In addition, the recent FIDELIO trial showed that treatment with the nonsteroidal MRA finerenone had lower risks of CKD progression and lower CV events in those with type 2 diabetes and CKD.56Resistant hypertension, defined as uncontrolled BP despite using three antihypertensive medications, one of which is a diuretic, is common with CKD.57 Sodium-glucose cotransporter 2 inhibitors also have been associated with significant reductions in home BP in individuals with type 2 diabetes mellitus, as well as patients with resistant hypertension, and have shown a laudable reduction in kidney disease progression and CV mortality.59Among patients with CV disease and CKD, there may be indications for drugs such as beta-blockers, though dual alpha and beta blockade may be superior in BP reduction due to its additional vasodilatory effect.60 The recommendation for nocturnal administration of antihypertensives has been increasing recently due to its hypothesized impact on reducing CV risk by lowering morning BP surges. A meta-analysis by Wang et al. showed nocturnal administration of BP medications resulted in a significant decrease in nocturnal SBP by 3.2 mm Hg  and a significant reduction in nocturnal DBP by 1.4 mm Hg . However, it showed no difference with regard to CV risk and all-cause mortality.61 The Hygia Chronotherapy trial was perhaps the largest study to examine this issue among more than 19,000 European patients who were hypertensive. The initial results showed a 45% reduction in CV risk despite only marginal BP reductions.62 Unfortunately, issues with their study protocol and overall conclusions came to light and the authors have since retracted the article.63 There is also evidence that nocturnal BP lowering can be hazardous with increased risk of myocardial and cerebral infarcts, particularly in elderly populations.64 Given the lack of CKD patients in these studies and uncertainty over benefit versus harm, no firm recommendations can be made regarding nighttime ingestion of antihypertensive agents.5Diurnal variation of BP higher in the early morning, followed by a decrease in BP later in the evening to night, particularly during sleep, is well described.5 This stems from a lack of studies targeting different BP goals in the kidney transplant population and concerns over eGFR decline, AKI, and incident CKD among those in the intensive BP arm of the SPRINT trial. Kidney transplant recipients with a solitary, denervated kidney purportedly could be placed at increased risk of such events with intensive BP lowering, though this has not been substantiated by clinical data.Different from the non-transplant CKD hypertension guidelines, the most recent 2021 KDIGO CKD hypertension guidelines state that a BP target < 130/80 mm Hg remains a reasonable goal for kidney transplant recipients.65Similar to the non-transplant CKD population, HBPM and ABPM should be used to complement OBP measurements for hypertension management. Recommended first-line antihypertensives include ARBs and CCBs. Dihydropyridine CCBs  are typically favored in the immediate perioperative period until kidney function stabilizes. Importantly, non-dihydropyridines  might interfere with the metabolism of immunosuppressant medications, particularly the calcineurin inhibitors cyclosporine and tacrolimus, as well as the mammalian target of rapamycin inhibitors sirolimus and everolimus, and careful monitoring of their drug levels is required.5 The mechanism for ARBs and reduced graft loss is not well understood. Ibrahim et al. showed losartan use was associated with less interstitial expansion, a precursor to graft fibrosis, though this was not statistically significant.66 Importantly, ARB use was well tolerated in kidney transplant recipients with minimal hyperkalemia.Meta-analyses have shown dihydropyridine CCB and ARB use were associated with a 38% and 65% reduction in graft loss, respectively, over a mean follow-up of 25 months, while non-dihydropyridines had no effect.Hypertension management in CKD lowers incident CV risk and reduces kidney disease progression. Existing guidelines have moved closer to consensus BP targets and place more emphasis on accurate BP measurements and more dependence on home and ABPM. Pharmacologic therapies offer varying degrees of risk reduction in CKD, and lifestyle interventions should be encouraged to augment these health benefits. Most importantly, patient engagement with out-of-office BP measurements, as well as more informed and shared decision making, will lead to long-term successes.The goal blood pressure for hypertension management in chronic kidney disease is < 120/80 mm Hg to reduce cardiovascular disease risk.Masked uncontrolled hypertension is highly prevalent in CKD patients, and out-of-office measurements such as home or ambulatory blood pressure monitoring are needed for diagnosis.Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are first-line for hypertension treatment in proteinuric CKD.Thiazide and thiazide-like diuretics have a role in hypertension management even in advanced kidney disease.


This report calls attention to the potential risks of diminished kidney function when administering immune globulin (IG). The goal is to increase awareness of chronic kidney disease (CKD) and kidney function impairment in patients receiving IG and provide recommendations for screening, monitoring, and management to promote risk prevention and mitigation.Human IG preparations for intravenous (IVIG) or subcutaneous (SCIG) administration are the mainstay of treatment in patients with primary immunodeficiency diseases. Increasingly, IVIG at high doses  is also used as a treatment for a variety of autoimmune and inflammatory conditions. Although some autoinflammatory disorders respond to a single course of IVIG therapy, the majority of patients require long-term, regular infusions, thereby increasing the overall risks. Often, both patients and physicians treating adults with IG are unaware of underlying CKD or kidney function impairment. This lack of awareness constitutes a major risk factor for potential worsening, particularly when using high doses of IVIG. Therefore, screening of all patients for CKD and kidney function impairment before the use of IG is essential. Identification of the cause of kidney impairment is strongly encouraged, as IG therapy may need to be modified.As detailed here, there are potential risks to patients with impaired kidney function with administration of IG, particularly at high doses. Product selection, volume, route of administration, and rate of infusion may impact those with compromised kidney function. Therefore, screening of all patients for CKD and kidney function impairment before the use of IVIG and SCIG, as well as ongoing monitoring and management, is critical. As with all potential adverse drug reactions, the best approach is to prevent them. Clinicians should evaluate all patients receiving immunoglobulin (IG) for underlying chronic kidney disease (CKD) and kidney function impairment on a regular basis; this is of critical importance in patients receiving high-dose intravenous IG.If CKD or kidney function impairment is identified, patients receiving IG should be closely monitored and managed to prevent further damage to kidney function.Identification of the cause of CKD or kidney function impairment is strongly encouraged, if feasible, as IG therapy may need to be modified.1 Administration of IG is an essential and life-saving therapy as these patients are unable to mount an effective immune response against infections. All IG products currently approved by the Food and Drug Administration (FDA) include an indication for IG replacement in PIDDs.2 Treatment with IG has also been FDA approved for a variety of autoimmune and inflammatory conditions, including immune thrombocytopenic purpura (ITP), chronic inflammatory demyelinating polyneuropathy (CIDP), dermatomyositis (DM), and multifocal motor neuropathy (MMN).3 Because of its immunomodulatory and anti-inflammatory effects, IG is also frequently administered off-label for a number of rare disorders and provides significant benefit in both acute and chronic conditions as a steroid-sparing agent and maintenance therapy.3 In the US, more than 75% of IVIG is administered to patients with autoimmune or inflammatory conditions.4 Depending on the specific autoimmune or inflammatory disorder being treated, typically high-dosage regimens and frequencies are used. Although some disorders can respond to a single course of IG therapy, the majority of patients require long-term, regular (weekly or monthly) infusions, thereby increasing overall risks.Human immune globulin (IG) preparations for intravenous (IVIG) or subcutaneous (SCIG) administration are the mainstay of treatment in patients with primary immunodeficiency diseases (PIDDs) as a replacement therapy.3 The use of IVIG has also rarely been associated with serious systemic adverse reactions, including kidney failure.3In many instances, IG has been life-saving; however, administration of IG can also lead to mild, as well as severe, adverse reactions, including aseptic meningitis, thromboembolic events, hemolytic reactions, and anaphylaxis.5 This report is focused on the potential risks with use of IVIG in patients with impaired kidney function. The goal is to increase awareness and provide recommendations for assessment, monitoring, and early treatment to promote risk prevention and mitigation.Approved IG products are manufactured via a fractionation process of pooled plasma from thousands of screened donors and undergo complex pathogen inactivation and purification steps to optimize product safety while ensuring preservation of functional activities.2 for at least 3 months .7 The different stages of classification of CKD form a continuum  group has published guidelines that define chronic kidney disease (CKD) as kidney damage and/or a decreased glomerular filtration rate (GFR) of less than 60 mL/min/1.73 montinuum . By itseStage 1: kidney damage  with normal or increased GFR (>90 mL/min/1.73 m2)Stage 2: kidney damage  with mild reduction in GFR (60-89 mL/min/1.73 m2)Stage 3a: mild to moderate reduction in GFR (45-59 mL/min/1.73 m2)Stage 3b: moderate reduction in GFR (30-44 mL/min/1.73 m2)Stage 4: severe reduction in GFR (15-29 mL/min/1.73 m2)Stage 5: kidney failure Abbreviation: GFR, glomerular filtration rate. Adapted with permission from reference 8 Approximately 15% of adults in the US (or 37 million people) are estimated to have CKD .9 Worldwide, prevalence is estimated at 8% to 16% in adults.8 Patients with CKD in stages 1 to 3 are generally asymptomatic. Most (9 in 10) adults are unaware of their CKD status, and about 2 in 5 people with severe CKD who are not on dialysis are unaware of underlying impaired kidney function.9 Diabetes mellitus and hypertension are the major causes of CKD in adults in developed countries.10 People may not feel ill or notice any symptoms until CKD is advanced.9 Therefore, recognition of the increased risk of CKD is vital. Risk factors include advanced age, family history of kidney disease, history of AKI, reduced nephron mass (history of nephrectomy or low birth weight), kidney damage with normal or increased GFR (>90 mL/min/1.73 m2), and genetic traits.10 In addition, exposure to diseases, conditions, and/or medications that cause CKD  is also a risk factor.10CKD is an increasing public health issue in global populations.9 Key risk factors for CKD are also increasing in prevalence, including obesity, which predisposes individuals to diabetes mellitus and hypertension . The risks for all noncommunicable diseases increase with elevated body mass index.11 The prevalence of obesity worldwide has nearly tripled since 1975, and more than 1.9 billion adults are considered overweight (approximately 39% of men and 40% of women).11 Once considered a problem of high-income countries, overweight and obesity are now on the rise in low- and middle-income countries, particularly in urban settings. As a result, CKD prevalence is expected to increase in parallel.CKD is viewed as a significant contributor to the rising worldwide noncommunicable disease burden.8 This lack of awareness on the part of patients and their physicians is a major risk factor for worsening of the disease. Therefore, screening of all patients for CKD before use of IG, as well as ongoing monitoring and management in patients with CKD, is essential. In addition, identifying the cause of the CKD is strongly encouraged; IG treatment may need to be modified according to the etiology of the impaired kidney function, which can influence the prognosis and relative importance of risk factors.7As emphasized in the previous section, the majority of adults are unaware that they have CKD.12-20 Dosing of IVIG and SCIG for replacement therapy in patients with PIDDs ranges from 300 to 800 mg/kg body weight.3 Utilization of IG has also been approved for several systemic autoimmune disorders owing to its immunomodulatory and anti-inflammatory effects, albeit at much higher doses  than those used for replacement therapy in PIDDs.21-25 In September 2008, FDA approved the first IVIG therapy for CIDP.27 Utilization of IVIG in CIDP was based on positive results in acute Guillain-Barré syndrome, as these disorders appear to be variants of the same immune-mediated inflammatory disorder of the peripheral nervous system.28-30 In 2012, IVIG was also approved for MMN.32 In addition to these approved, on-label uses, high-dose IVIG is also widely used off-label for a number of autoimmune and inflammatory disorders.3Individuals with PIDDs are treated with IG to replace low or missing levels of antibodies and reduce infection rates.34 For patients who have experienced adverse reactions to IVIG, including kidney complications, SCIG may represent an acceptable alternative. Like IVIG, SCIG is also used off-label to treat autoimmune diseases.35 One of the main challenges with SCIG in autoimmune diseases is administering larger doses (as compared to replacement doses) and the limited volume of IG that can be infused at one time.36 However, because infusions can be given in the convenience of a home setting, patients adapt to more frequent infusions  with the added benefit of fewer systemic reactions and a steady, less fluctuating serum immunoglobulin G (IgG) level. The decision to utilize SCIG or IVIG is dictated by each patient’s disease characteristics, treatment goals, lifestyle, and insurance mandates.34 Because this report is focused on kidney complications associated with IG, local complications associated with SCIG are not covered.Administration of IG via subcutaneous infusion, or SCIG, has also been approved in the US for PIDDs and select neurological indications, including CIDP.5 Various excipients are added to stabilize IG products and prevent aggregation and dimer formation, including human albumin, glycine, polyethylene glycol, and sugars such as sucrose, maltose, and glucose.37 These excipients, also known as stabilizers or additives, have clinical implications.39 A full comparative analysis of all IG products is beyond the scope of this article; however, a comprehensive comparative chart of IG products is available from Managed Healthcare Associates, Inc., at https://bit.ly/32xBrEo (link provided with permission).Currently, all IG products are manufactured via a fractionation process in which plasma is pooled from thousands of screened donors and then undergoes highly complex, rigorous manufacturing processes ensuring pathogen inactivation, preservation of functional activities, and product safety and efficacy.35 The relationship between IVIG stabilized with sucrose and kidney impairment, including AKI, kidney failure, osmotic nephrosis, and kidney insufficiency, is now well known.39-42 Sucrose causes kidney injury as it enters tubular epithelial cells via pinocytosis. Epithelial cell swelling and cytoplasmic vacuolization occur as a result of incorporation of sucrose into lysosomes, which in turn causes narrowing of the tubular lumina. Thus, AKI induced by sucrose-containing IVIG may be related to the toxic action of sucrose, which causes degradation of the proximal tubular epithelium and kidney injury.39 The incidence of IVIG-related kidney impairment cannot be precisely determined, but the numbers of reported cases suggest a significantly lower incidence for products containing stabilizers other than sucrose.39Onset of kidney impairment after IG administration is rare but is one of the most significant adverse reactions related to IG.43 Almost 88% of these reports were associated with the use of sucrose-stabilized products. The French Regional Pharmacovigilance Center reported 49 cases of AKI that occurred between 1992 and 1998, all of which were associated with sucrose-stabilized preparations.44 This finding was initially reported in 1987 as acute cryoglobulinemic renal failure.45 Incidence of kidney impairment declined after FDA required all IVIG manufacturers to revise their prescribing information to include a black box warning.43 These data also triggered modifications of the stabilizers used in IVIG products and the development of sucrose-free products.From 1981 (when IVIG was introduced) to November 1998, FDA received 114 reports worldwide of impaired kidney function and AKI associated with IVIG. The majority of patients recovered kidney function, but 17 deaths were reported following kidney failure.39 For example, the clinical effects of sugar-stabilized IVIG preparations were assessed by Chapman et al.46 While being treated with a sucrose-stabilized IVIG preparation, a 44-year-old male developed AKI requiring hemodialysis. After his kidney function normalized, the patient was switched to a d-sorbitol–stabilized IG without any resulting kidney complications. d-Sorbitol is primarily metabolized within the liver and, to a lesser degree, in the kidney and other tissues. Intracellular accumulation of sorbitol is well regulated within the kidney by the complementary actions of aldose reductase and sorbitol dehydrogenase, which may account for the relatively low incidence of AKI with sorbitol-stabilized IVIGs.47-49Unfortunately, some publications regarding IVIG stabilizers group sugars together and imply that their properties and clinical effects are all similar to those of sucrose, which is not accurate.50 IVIG products stabilized with maltose are well tolerated because maltase, the enzyme that hydrolyzes maltose to glucose, is present in the brush border of proximal convoluted renal tubules.49 Animal experiments have demonstrated that, unlike sucrose, for which more than 60% may be excreted unchanged in the urine, maltose is mostly metabolized, with less than 5% excreted unchanged.51 Conversion of maltose to glucose occurs intracellularly in the kidney; thus, maltose does not increase glucose levels in the blood. Although IVIG preparations stabilized with maltose have been associated with falsely high blood glucose meter readings in older systems based on glucose dehydrogenase pyrroloquinoline quinone or glucose-dye-oxidoreductase methods,52 this issue has largely been resolved with the use of modern glucose-specific blood monitoring methods.Maltose is a water-soluble disaccharide. Unlike sucrose, maltose is metabolized by kidney cells.38 Excipient-grade d-glucose (dextrose) is frequently used for its various chemical properties  and its ability to improve the stability of oxidation-sensitive active materials.38 Intravascular glucose is rapidly distributed to extracellular fluid and is expediently catabolized or converted to glycogen.49 Although glucose, when used as an excipient in IG preparations, does not appreciably increase glucose levels in blood, excessive glucose accumulation can have negative effects on proximal kidney tubules in humans.49 Because IV glucose infusion is known to produce a rapid increase in blood glucose and insulin levels in normal individuals, patients with diabetes may be at risk of kidney damage following administration of IVIG products stabilized with glucose.53Glucose is a monosaccharide that possesses a free ketone or aldehyde group, allowing it to donate electrons to other molecules and, thereby, act as a reducing agent.54 Common manifestations include hematuria and mild to moderate proteinuria.55 The serum creatinine level usually peaks around day 5 . Oliguric kidney failure is more common than nonoliguric kidney failure.55 In addition to risk factors directly related to product stabilizers, specific characteristics may predispose some patients to kidney complications following the use of IVIG .When kidney complications do occur, kidney insufficiency typically develops within 1 week (1-10 days) of the initiation of IVIG treatment.56 However, in approximately 40% of patients, at least 1 day of hemodialysis is required.41 Most patients recover within 2 weeks of hemodialysis.57 Despite the eventual positive outcomes observed in most patients with IVIG-related kidney impairment, AKI may progress to CKD or kidney failure.55 Death may occur in 8% to 15% of these patients, but most have additional underlying conditions that make it difficult to determine precise causality.58In most patients, AKI is reversible within 4 weeks  of discontinuation of the IVIG.59 The sodium chloride content ranges between 0% and 2%, and low-salt formulations are available for patients who are sensitive to fluid and/or salt. Products with a higher IVIG concentration may be advisable in patients with heart failure who may not tolerate excess fluid volume.59 Interestingly, high-dose IVIG has been successfully utilized for the suppression of panel reactive antibodies in the management of highly sensitized patients with late-stage CKD receiving dialysis while awaiting kidney transplantation.60Many components other than stabilizers may influence tolerability in patients with kidney impairment, especially in those with late-stage CKD. For example, products vary in their osmolality, pH, and salt content. Osmolality ranges between 192 and 1,250 mOsm/L depending on the product, and the osmolality of the product must be considered when treating patients with impaired kidney function who may not tolerate a large osmotic load.As with all potential adverse drug reactions (ADRs), the best approach is avoidance. To facilitate increased awareness among clinicians who administer IG, we have developed recommendations for screening, monitoring, and management for CKD to promote risk prevention.58 Therefore, all patients receiving IG should be screened for CKD risk factors and serum creatinine levels should be obtained before initial IVIG or SCIG administration , diabetes mellitus, hypertension, obesity, cardiovascular disease, volume depletion (dehydration or hypervolemia), autoimmune disease, infections, paraproteinemia, and concomitant and/or past nephrotoxic drug usage .39,40,43stration .35 The volume infused with each treatment is much lower with SCIG, thereby mitigating kidney toxicity. However, we propose screening for and management of potential kidney impairment in all patients receiving IG because of the relative lack of awareness of this widespread disorder.61To date, there have been no reports of SCIG-induced kidney toxicity.Impaired kidney function can progress to late-stage CKD, kidney failure, and even death with the use of IVIG and SCIG. Early detection of CKD, especially in patients on high-dose IVIG therapy, is critical for initiating timely interventions and modifications, thus limiting the potential for further reduction in GFR. For patients with a history of impaired kidney function or risk factors for CKD, ongoing monitoring and management are recommended .One of the key elements of monitoring is routine laboratory evaluation of GFR at baseline with repetition at least quarterly for those with mild to moderate kidney disease and at least monthly for those with severe renal disease . In addiTo better understand the impact of kidney disease, specifically in relation to IVIG administration, illustrative case examples including case presentation and management are provided below.2) that required a 2-week stay in the intensive care unit (ICU). She received daily hemodialysis in the ICU and was subsequently moved to the hospital floor and discharged 1 week later with an improved GFR of 63 mL/min/1.73 m2. However, because of her recent change in status, the physician recommended switching to SCIG to reduce the potential likelihood of any systemic adverse events, including any further decrease in kidney function. The patient and her family were trained on SCIG administration, and nursing staff plan to continue to assist the patient with the transition over the next few months. If her estimated GFR decreases further and/or she experiences any ADRs related to SCIG treatment, she will be reevaluated.A 65-year-old African American female was diagnosed with common variable immunodeficiency later in life following repeated upper respiratory tract infections. She had been stable on replacement IVIG for the last 10 years. She was recently hospitalized for a severe skin and soft tissue infection in her right upper arm and received vancomycin and piperacillin/tazobactam. An ADR to the antibiotic regimen resulted in AKI , at a rate of 300 mL/h, on a monthly basis for approximately 15 years. Over the last 2 years, he gained a considerable amount of weight and was recently diagnosed with diabetes. He was prescribed metformin and is also trying to control his blood sugar with diet and exercise. In addition, the patient reported that he has very low energy and often feels depressed, which limits his motivation to exercise and maintain a healthy diet.2, indicating that he had a moderate reduction in GFR. According to the recommendations, his kidney function should be monitored quarterly. To date, he has tolerated IVIG without any ADRs. However, the nursing staff were advised to decrease his IVIG infusion rate from 300 to 100 mL/h. In addition, he will receive 500 mL of hydration with each infusion (250 mL before and 250 mL during the infusion). To reduce any volume overload, his infusions will also be given every other day rather than on consecutive days. His diabetes will be closely monitored, and he has been referred to a weight loss clinic, as well as a therapist, to manage the onset of depression related to his recent diagnosis and ongoing struggles with weight. If his estimated GFR decreases further and/or he experiences any ADRs related to treatment, he will be reevaluated.Following the screening recommendations, a kidney function panel was obtained. The patient’s estimated GFR was 42 mL/min/1.73 m43 All currently approved IVIG products in the US still include this black box warning. In the FDA medical bulletin issued by Epstein et al43 in 1999, the authors stated that “reduction in dose, concentration, infusion rate, or all of these in patients at risk of acute renal dysfunction has been proposed in order to reduce the risk.” Like the authors of the current report, they also recommended baseline kidney function measurements before IVIG infusion with repeated measurements at appropriate intervals for those at increased risk of kidney impairment.43As a result of early reports of renal failure with IVIG, mostly related to sucrose stabilizers, FDA required that all IVIG manufacturers revise their prescribing information to include a black box warning stating that renal dysfunction, acute renal failure, and osmotic nephropathy may occur with IVIG.62 Although most systemic adverse effects present within 10 days of IVIG infusion,54 it is also important to consider the potential negative impact to kidney function following long-term therapy. In a 2017 report by Levine and colleagues,63 the authors retrospectively analyzed laboratory data from 166 patients who had received 12 months of high-dose IVIG infusions for neurological disorders. In these patients, the GFR measures at 6 and 12 months were compared to baseline values and then averaged to determine the effects on GFR of long-term, high-dose therapy. It is important to note that patients with a history of renal issues were excluded from the study population; the investigators also excluded patients on other drugs that could confound the analysis, including steroids and immunosuppressive medications. In the overall study population, approximately 10.34% of patients had a drop of more than 20% in GFR over 12 months. In addition, for patients receiving Gamunex (Grifols), Privigen (CSL Behring AG), or Bivigam (ADMA Biologics), there was a significant risk of a decrease of more than 20% in GFR. In a study population that was chosen from otherwise healthy individuals, without kidney impairment, diabetes, or potentially nephrotoxic medications, these findings are particularly significant.63 The findings emphasize the need to initially evaluate and continue to monitor kidney function in all patients receiving long-term, high-dose IG.The highest rates of systemic adverse events with IVIG, including kidney complications, occur in adult patients with autoimmune, neurological, or hematological disorders receiving high-dose IVIG.64 The use of IG to treat autoimmune diseases in older individuals is increasing in prevlaence.65 In a study by Lozeron and colleagues,65 use of IVIG was examined in older individuals who were treated for autoimmune neuromuscular disease. In this study, in patients 60 years of age or older, high-dose, chronic administration of sucrose-free IVIG was associated with ADRs, including kidney failure. The authors noted that higher infusion rates may have had a role and suggested that specific studies may need to be conducted to further explore this correlation. They also recommended that special attention be paid to the maximum daily IVIG dose in older patients.65One of the key risk factors for kidney impairment is advanced age (≥65 years) .10,64 ThAs detailed herein, there are potential risks related to kidney function during and/or following administration of IG. The goal of this report is to increase awareness of impaired kidney function in patients receiving IG and provide recommendations for screening, monitoring, and management for kidney disease to promote risk prevention and mitigation. Clinicians should evaluate all patients receiving IG for underlying kidney function impairment and CKD; this is of critical importance in patients receiving high-dose IVIG, especially in older patients. If CKD or impaired kidney function is identified, patients receiving IG should be closely monitored and managed to prevent further damage. Identification of the cause of CKD or kidney impairment, if feasible, is strongly encouraged, as IG therapy may need to be modified.The majority of adults with CKD or kidney function impairment are unaware of their status. This lack of awareness on the part of patients and their physicians is a major risk factor for worsening of the disease following administration of IG. Therefore, screening of all patients for CKD or kidney function impairment before use of IG, as well as ongoing monitoring and management for patients in whom CKD or kidney function impairment has been identified, is essential. As with all potential ADRs, the best approach is avoidance.zxac139_suppl_Supplementary_Appendix_S1Click here for additional data file.


Hypertension (HTN) is common in chronic kidney disease (CKD), and it may aggravate CKD progression. The optimal blood pressure (BP) value in CKD patients is not established yet, although systolic BP ≤130 mmHg is acceptable as a target. Continuous BP monitoring is essential to detect the different variants of high BP and monitor the treatment response. Various methods of BP measurement in the clinic office and at home are currently used. One of these methods is ambulatory BP monitoring (ABPM), by which BP can be closely assessed for even diurnal changes.We conducted a non-systematic literature review to explore and update the association between high BP and the course of CKD and to review various BP monitoring methods to determine the optimal method for BP recording in CKD patients. PubMed, EMBASE, Google, Google Scholar, and Web Science were searched for published reviews and original articles on BP and CKD by using various phrases and keywords such as "hypertension and CKD", "CKD progression and hypertension", "CKD stage and hypertension", "BP control in CKD", "BP measurement methods", "diurnal BP variation effect on CKD progression", and "types of hypertension." We evaluated and discussed published articles relevant to the review objective. Before preparing the final draft of this article, each author was assigned a section of the topic to read, research deeply, and write a summary about the assigned section. Then a summary of each author's contribution was collected and discussed in several group sessions.Early detection of high BP is essential to prevent CKD development and progression. Although the latest Kidney Disease Improving Global Outcomes (KDIGO) guidelines suggest that a systolic BP ≤120 mmHg is the target toprevent CKD progression, systolic BP ≤130 mmHg is universally recommended.ABPM is a promising method to diagnose and follow up on BP control; however, the high cost of the new devices and patient unfamiliarity with them have proven to be major disadvantages with regard to this method. Chronic kidney disease (CKD) is a global health problem, with an estimated prevalence of 11-13% . CKD canThe prevalence of hypertension (HTN) in CKD patients is 80-85%, which is significantly higher than in the general population (28.5%) . This di2 to 92% in those with an eGFR of 30 ml/min/1.73 m2 [Optimum BP control is essential in CKD patients to prevent CKD progression and other complications . HTN pre/1.73 m2 ,13. The /1.73 m2 . In addi/1.73 m2 ,16. The /1.73 m2 ,17. Furt/1.73 m2 .Mercury-based sphygmomanometer devices are the primary BP measuring techniques currently used. However, automatic, ambulatory BP monitoring (ABPM), and ultrasonic-based methods have recently gained currency as BP recording techniques. Each technique has its own limitations, advantages, disadvantages, and abilities to detect BP variations and assess the response to treatment. In light of this, we aim to discuss and update the effect of BP on CKD progression and explore the various methods of BP recording in CKD patients.CKD and HTNCKD is classified into five main stages and further subdivided into subgroups according to the GFR value and albuminuria . There iIn their study, Aggarwal et al. found that in non-tight glycemic control diabetic patients with CKD stage 3 or more, intensive systolic BP management (130 mmHg) lowers all-death causes when compared to a BP of 140 mmHg . AnotherThe International Society of Hypertension (ISH) has modified the worldwide practice guidelines for HTN diagnosis and management in adults aged ≥18 years . The guiIn CKD, careful HTN control is critical to slow the progression of the disease. The importance of BP measurement and strict BP control are emphasized in the recent Kidney Disease Improving Global Outcomes (KDIGO) guidelines on BP therapy in CKD . AlthougTypes of HTNPrimary  and secondary HTN are the two basic types of HTN. Primary HTN accounts for the majority of cases (95%), and it has no known cause. Thyroid disorders, sleep apnea, excessive alcohol use, obesity, high-salt food consumption, tumors, adrenal hyperfunction, medicines, kidney illness, and other factors are all linked to secondary HTN. In addition to these HTN categories, other types such as isolated systolic, malignant, resistant, labile, and white-coat HTNs have also been identified, and these have their own particular diagnostic criteria.Isolated systolic HTN is diagnosed when the systolic BP is >140 mmHg, and the diastolic BP is ≤80 mmHg. Isolated systolic HTN is more widely prevalent in people aged >65 years, and it is most probably due to arterial wall stiffness . The incWhite-coat and labile HTN are types of HTN that are not uncommon. These terms have been alternatively used to label cases with high normal BP levels. These cases are more likely to have HTN, although they may indicate an increase in BP as a physiological response. Labile HTN occurs in almost every individual, and it can be related to BP record changes due to factors such as stress, environment, food, etc. On the other hand, a white-coat HTN diagnosis is usually given to subjects who have high BP levels when measured by a medical professional but have normal BP levels when recorded in other settings. Therefore, due to the variability of BP values and the effect of white-coat, the American Heart Association recommends that BP measurement must be conducted a minimum of three times during different times of the day for a precise HTN diagnosis. However, some physicians prefer to reassess BP 5-10 minutes after the first high BP record in the same setting in a single visit. White-coat HTN was reported in 28.8%, and masked HTN was noted in 7% of CKD patients in one study , causingNight-time HTN and non-dipping night BP patterns are the other types that may negatively affect end organs. Non-dipping is not a specific independent risk factor that negatively impacts CKD outcomes, although it is a recognized risk factor for CKD progression. However, the early studies on the subject were not controlled for proteinuria. Proteinuria has been linked to BP non-dipping, and proteinuria is a risk factor for CKD deterioration . As a re2) is characterized by endothelial dysfunction, and these endothelial alterations are strongly related to HTN [HTN is a well-known cause of CKD, and CKD is also a cause of secondary HTN. HTN associated with CKD causes is multi-factorial. Sodium dysregulation , decreasd to HTN . Additiod to HTN , implyind to HTN . As HTN d to HTN ,43. DeteGeneral considerations for high-BP managementThe number of hypertensive patients aged between 30 and 79 years has doubled in the recent decades, increasing from an estimated 317 million men and 331 million women in 1990 to about 626 million women and 652 million men in 2019. More than 50% of these hypertensive individuals (720 million) received no treatment in 2019 . GloballSetting optimal BP targets has a sizeable clinical impact  on morbiBP measurement methods and recommendationsBP measurement is usually conducted by a doctor or nurse with a sphygmomanometer in their clinics; however, the recent wide availability of semi or fully automatic machines has enabled medical professionals or patients themselves to measure BP. Currently, there are four methods to measure BP.A. Clinic Office BP Measurement MethodsClinic office BP recording needs to fulfill specific requirements, which are summarized in Table 1. Auscultatory method: this method is the gold standard for clinic office BP recording. This mercury-based device used to measure BP is currently sparingly used and even abandoned in various countries due to the toxicity risk associated with mercury . New hyb2. Automated office BP monitoring: novel non-mercury-based oscillometric devices are now widely used for BP recording in the clinic office , and othB. Home Self-BP Monitoring Methods1. Intermittent home self-BP measurement method: intermittent BP monitoring by fully automatic electronic devices at home is widely practiced in developed countries to confirm HTN and follow up on the response to treatment. Furthermore, the intermittent home BP recording method is a more suitable and acceptable alternative to the ABPM method to differentiate between HTN phenotypes . Higher 2. ABPM method: ABPM has been in use for more than 30 years. The ABPM technique is used to measure BP every 15 minutes during the day and every 30 minutes during the night while subjects are conducting their daily activities . One of It has been noted that abnormal ABPM pattern is typically related to proteinuria than to deterioration of eGFR in CKD patients . Also, iC. Central BP Monitoring MethodCentral BP monitoring is an invasive BP recording technique. This technique is performed by inserting an arterial catheter with tonometry at the carotid artery . AlthougD. Smartphone and Other Device-Based BP Monitoring MethodThe smartphone-based method of BP recording is a recently invented way to measure BP via smartphone applications ,61. ThisRecently, Degott et al., based on their analysis of 353 paired recordings from 91 persons, have reported that "the smartphone embedded OptiBP cuffless mobile application achieves the validation requirements of the Association for the Advancement of Medical Instrumentation (AAMI), the European Society of Hypertension (ESH), and the International Organization for Standardization (ISO), universal standards in a general population for the measurement of diastolic BP and systolic BP" . AnotherRecommendations based on current guidelinesIn November 2015, the U.S. Preventive Services Task Force (USPSTF) accepted the clinic office's repeated BP recording method to diagnose HTN and advised that BP be recorded outside of the clinic office to confirm HTN before treatment and follow-up . The USPAutomatic BP measuring devices with multiple records in the physician clinic are better at overcoming white-coat HTN overdiagnosis compared to the usual clinic office BP recording method . NumerouBP measurement by ABPM or home BP recording is highly recommended to diagnose and manage HTN in the newly published guidelines ,15,17. AGender and CKD progressionSeveral guidelines have suggested that early HTN detection and prompt treatment can delay the CKD progression and decrease complications in both genders ,70. HoweBP measurement is essential for diagnosis and following up on the response to therapy. Accurate diagnosis and detection of the HTN phenotype are critical to preventing CKD complications development and progression. Despite the diversity of methods and devices for BP measurement, the mercury sphygmomanometer is still considered the gold standard. However, new devices are increasingly being used currently, but they are not highly accurate and need frequent calibrations. Although it appears that ABPM is the best method to confirm or rule out HTN and differentiate between various HTN phenotypes, its superiority over the other BP measurement methods is questionable and not clearly established. Therefore, new research projects are required to assess and explore the superiority of the ABPM technique.Clinicians should reach a consensus that a systolic BP level <130 mmHg in CKD improves all-cause mortality rates, despite the variations between the reported data. However, further studies are required to assess the link between the early detection and control of high BP levels and CKD development and progression patterns. We propose that tight control of BP at a level <130/80 mmHg is highly recommended and that ABPM is a highly reliable method for HTN diagnosis, especially in doubtful cases, and it is especially more effective in predicting CKD progression.


People with schizophrenia have a life expectancy that is 10–20 years shorter than the general population. The high incidence of metabolic syndrome, cardiovascular disease and diabetes mellitus in this patient group are thought to be major – and potentially modifiable – factors contributing to this premature mortality. Therefore, annual monitoring of physical health parameters is recommended by organisations including the Scottish Intercollegiate Guidelines Network (SIGN). The SIGN guideline on schizophrenia advises that the following parameters are checked annually for patients with schizophrenia who are on anti-psychotics: ECG, blood glucose, lipid profile, prolactin, BMI/weight, smoking status and blood pressure. Traditionally, this monitoring is overseen in the community by general practitioners. This audit aimed to capture how the COVID-19 pandemic impacted on the annual physical health monitoring of patients under the care of NHS Borders Community Rehabilitation Team.A retrospective audit was performed by reviewing notes of the 100 patients on the NHS Borders Community Rehabilitation team caseload. Notes from the years of 2019, 2020 and 2021 of all 100 patients on the caseload were reviewed, for documentation of the following seven parameters as recommended by SIGN: ECG, blood glucose, lipid profile, prolactin, BMI/weight, smoking status and blood pressure. Results were then entered manually into a secure spreadsheet. Permission for this audit was granted by NHS Borders.Initial results for the parameters of: ECG, blood glucose, lipid profile and prolactin levels demonstrate that routine monitoring of all four domains has decreased since the start of the COVID-19 pandemic. In 2019 the following numbers of patients had monitoring in these domains: ECG 56 (56%); blood glucose 84 (84%); lipid profile 74 (74%) and prolactin levels 62 (62%).During 2020, the number of patients having monitoring in all four domains fell: ECG 31 (31%); blood glucose (72%); lipid profile 64 (64%) and prolactin levels 48 (48%). During 2021, monitoring levels remained low: ECG 30 (30%); blood glucose 71 (71%); lipid profile 62 (62%) and prolactin levels 43 (43%).Data collection for the parameters of blood pressure, BMI/weight and smoking status is ongoing.Initial results indicate that the COVID-19 pandemic has negatively impacted on the routine physical health monitoring of patients under the care of the community rehabilitation team in NHS Borders. These results imply opportunities to treat and prevent conditions such as diabetes mellitus and hypercholesterolemia are being missed, further perpetuating an existing health inequality for patients with severe and enduring mental illness.


Randomised controlled trial showed that dulaglutide can reduce the risk of atherosclerotic cardiovascular disease (ASCVD) in patients with type 2 diabetes mellitus (T2DM), but the underlying mechanisms remain unclear. This study aimed to investigate the effect of dulaglutide on the number and function of endothelial progenitor cells (EPCs) in the peripheral blood of patients with T2DM and its role in improving arterial elasticity, so as to determine potential mechanisms of preventive effect of dulaglutide on ASCVD.+CD133+KDR+ EPCs and the brachial–ankle pulse wave velocity (baPWV) of the participants were measured, and EPC proliferation, adhesion, migration, and tubule formation were assessed in vitro.Sixty patients with T2DM were treated with 1000 mg/day of metformin and randomly divided into two groups for 12 weeks: metformin monotherapy group , and metformin combined with dulaglutide group . Before and after treatment, the number of CD34P > 0.05). In MET-DUL group, nitric oxide (NO) levels and the number of EPCs increased after treatment (P < 0.05), while the levels of C-reactive protein (CRP), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), advanced glycation end products (AGEs), and baPWV decreased (P < 0.05). EPC proliferation, adhesion, migration, and tubule formation abilities were significantly enhanced (P < 0.05). Correlation analysis showed that in MET-DUL group, the changes in CRP, IL-6, TNF-α, and AGEs were negatively correlated with the number of EPCs and their proliferation and migration abilities (P < 0.05). Body weight, NO, CRP, and IL-6 levels were independent factors affecting the number of EPCs (P < 0.05). The changes in number of EPCs, proliferation and migration abilities of EPCs, and NO and IL-6 levels were independent influencing factors of baPWV changes (P < 0.05).There were no significant differences in the number and function of EPCs and baPWV changes in MET group (Dulaglutide can increase the number and function of EPCs in peripheral blood and improve arterial elasticity in patients with T2DM; it is accompanied by weight loss, inflammation reduction, and high NO levels. Dulaglutide regulation of EPCs may be a mechanism of cardiovascular protection. Atherosclerotic cardiovascular disease (ASCVD) is a common complication and a leading cause of death in patients with type 2 diabetes mellitus (T2DM) . StudiesEndothelial progenitor cells (EPCs) are primordial cells derived from the bone marrow that can enter the peripheral blood circulation and differentiate into mature endothelial cells under certain conditions . EPCs maArterial elasticity, also known as arterial stiffness, refers to the ratio of arterial volume to pressure. It can reflect the changes of arterial structure and function and is an independent risk factor for premature cardiovascular morbidity and mortality ; furtherIn this study, we observed the effects of dulaglutide on baPWV and the number and function of EPCs in the peripheral blood of patients with T2DM. Furthermore, we analysed the possible relationship between dulaglutide and circulating EPCs and baPWV, so as to investigate the cellular biological mechanism of dulaglutide in improving vascular injury and provide a theoretical basis for determining the preventive effect of dulaglutide on ASCVD.2; and no intake of lipid-regulating drugs or a stable dose of lipid-lowering drugs for at least 6 months. Exclusion criteria were as follows: fasting C-peptide level was lower than 0.6 ng/ml; patient had acute metabolic abnormality; obvious abnormal function of heart, liver, or kidney; obvious gastrointestinal or pancreatic disease; medullary thyroid carcinoma or a family history of medullary thyroid carcinoma; serum triglyceride (TG) ≥ 5.6 mmol/l; and patient used corticosteroids, immunosuppressants, oestrogens, or exogenous cytokines, etc., in the past 6 months. This study was approved by the Medical Ethics Committee of the First Affiliated Hospital of Anhui Medical University (Ethics batch number P2020-01-12), and informed consent was obtained from all participants.Sixty patients with T2DM, all of whom met the World Health Organisation (WHO) 1999 diagnostic criteria for diabetes, were recruited between January 2020 and April 2021 in the Department of Endocrinology at the First Affiliated Hospital of Anhui Medical University . Inclusion criteria was as follows: age 18–65 years; male or female; diabetes duration ≤ 2 years with no ASCVD; received lifestyle intervention and 1000 mg/day of metformin  for at least 8 weeks; HbA1c 7.0–7.5% (53.0–58.5 mmol/mol); body mass index (BMI) 18.5–30 kg/mSpecialised personnel monitored the diet, exercise, and blood sugar levels of all participants. On the basis of maintaining the original lifestyle intervention, all participants were randomly divided into two groups: metformin monotherapy group  and metformin combined with dulaglutide group . The randomisation code was computer-generated by the study statistician, who assigned the next available randomisation number when informed of the next eligible participant. Participants in MET group received 2000 mg/day of oral metformin, while participants in MET-DUL group maintained the original metformin dose of 1000 mg/day and were injected subcutaneously with 1.5 mg of dulaglutide  once weekly before breakfast. Both groups were treated continuously for 12 weeks. In the MET group, the metformin dose was reduced to the maximum tolerance dose in participants who had gastrointestinal reactions. In the MET-DUL group, if participants had obvious gastrointestinal reactions after the first injection, their dulaglutide injection could be postponed for 3 days. If the gastrointestinal reactions worsened after the second injection, participants were immediately withdrawn from the study and were offered other treatment options.2) of each participant were measured on the day of their enrolment (0 week) and 12 weeks after treatment. Laboratory tests were performed with venous blood samples drawn from the median vein of participants’ elbows. Fasting blood glucose (FPG) levels were determined by the glucose oxidase method, HbA1c was detected with the use of a high-pressure liquid chromatography (HPLC). Triglyceride (TG) and total cholesterol (TCH) levels were measured by the enzymatic method. High-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were detected by the oxidase colorimetric method; serum NO by the nitrate reductase method; C-reactive protein (CRP) by the latex-enhanced scattering immunoturbidimetry assay; tumour necrosis factor α (TNF-α) and interleukin-6 (IL-6) by the double-antibody sandwich enzyme-linked immunosorbent assay (DAS-ELISA); and serum advanced glycation end products (AGEs), VEGF, and SDF-1α by ELISA.Participants fasted for 10 h in preparation for their physical examination and laboratory tests (7.00–8.00 a.m.). The height, weight, systolic blood pressure, diastolic blood pressure, and BMI defined as weight per height squared . The measurement time was selected on the day of enrolment (0 week) and 12 weeks after treatment, respectively.Participants fasted for 10 h before 2 ml of venous blood was drawn from the median vein of their elbows and placed into the ethylenediaminetetraacetic acid anticoagulant tube for examination (7.00–8.00 a.m.) at 0 and 12 weeks. The number of EPCs positive for CD34, CD133, and KDR was determined via flow cytometry following the previously-described method [g and 20 °C for 10 min. The mononuclear cell layer was separated, placed in EGM-2 culture medium  in fibronectin-coated plates pre-lined with fibronectin, and incubated in 5% CO2 at 37 °C. The morphological changes of the cells were dynamically observed under an inverted fluorescence microscope . After 2 weeks, adherent cells were incubated in 2.4 µg/ml of acetylated low-density lipoprotein solution for 1 h, which was fixed with 20 g/l paraformaldehyde, incubated in a lectin antibody solution for 1 h, and observed and photographed under the fluorescence microscope. The red and green double-stained cells were identified as EPCs  [Peripheral blood samples (20 ml) from participants at 0 and 12 weeks were placed in heparin tubes and diluted (1:1 in volume) with phosphate-buffered saline (PBS). Then, each sample received 10 ml of Ficoll-Paque separation solution and was centrifuged at 2000y EPCs’) .5 cells/ml and cultured for 72 h in a 96-well plate. Then, the EPC solution was incubated with 10 μl MTT solution (5 mg/ml) for 4 h and with 100 µl dimethyl sulfoxide under oscillation for 10 min after discarding the supernatant. The absorbance value (OD) of each well was measured using an enzyme-labelling instrument  at 490 nm.EPC proliferation was measured using the -2,5-dipheny-l-tetrazolium bromide; MTT) assay. Briefly, the adherent EPCs were digested with 0.25% trypsin and suspended in Dulbecco’s Modified Eagle Medium (DMEM) culture. The EPC solution was adjusted to 1 × 105 cells/ml and incubated at 37 °C for 2 h in a 96-well plate. The unadhered cells were absorbed and washed gently with PBS. Six replicate wells were prepared and performed for each sample. In each replicate, the adherent cells were counted under the microscope with five randomly-selected visual fields.EPCs’ adhesion ability (EAA) was determined using a previously-reported method . Briefly5 cells/ml. The EPC solution (100 μl) was added to the upper Transwell chamber , while 600 μl EGM-2 medium containing 50 μg/l VEGF was added to the lower chamber. After incubation at 37 °C for 12 h, the upper chamber was removed and the culture medium was discarded. The upper chamber was rinsed twice with PBS, fixed for 15 min with 4% paraformaldehyde, air-dried at room temperature (25 °C), and dyed for 30 min with 0.1% crystal violet. The non-migrated cells at the upper chamber were wiped gently with cotton swabs, rinsed thrice with PBS, and counted under a microscope with five randomly-selected visual fields [The adherent EPCs were digested with 0.25% trypsin and suspended in DMEM culture medium; the concentration of EPCs was adjusted to 1 × 10l fields .5 cells/ml) was transferred to a 96-well plate coated with Matrigel  and incubated at 37 °C for 24 h. Tubule formation was observed and photographed under a fluorescence microscope, and the total branch length of the vascular lumen in the visual field was calculated using ImageJ software  [The EPC solution (1 × 102) test. Pearson correlation analysis and multiple linear stepwise regression analysis were used to investigate the related factors affecting the number and function of EPCs before and after treatment with dulaglutide. These analyses were also used to understand the effects of clinical factors on baPWV changes to evaluate the predictive value of EPCs’ quantitative and functional changes on arterial elasticity changes. The change value  before and after treatment was calculated according to the index values observed at 0 and 12 weeks. Statistically-significant differences were set at P < 0.05.SPSS 19.0 software was used for statistical analyses. The measurement data were expressed as the mean standard ± deviation  , while BMI, blood pressure, blood lipid profiles, serum NO, VEGF, SDF-1α, CRP, TNF-α, IL-6, AGEs levels, number of EPCs in peripheral blood, EPA, EAA, EMA, ETF, and baPWV did not show significant differences at the end of the treatment , while serum NO, number of EPCs in peripheral blood, EPA, EAA, EMA, and ETF increased significantly (P < 0.05). However, there were no statistically significant differences in blood pressure, TCH, TG, LDL-C, HDL-C, or VEGF levels after treatment . However, there were no statistically significant differences in blood pressure, FPG, FCP, HbA1c, TCH, TG, LDL-C, HDL-C, serum VEGF, or SDF-1α between the two groups after 12 weeks , while ΔNO, ΔEPCs, ΔEPA, ΔEAA, ΔEMA, and ΔETF in the participants in MET-DUL group were significantly higher than those in the MET group (P < 0.05). The other observed indexes did not show statistically significant differences between the two groups in their change values , ΔFPG , ΔCRP , ΔTNF-α , ΔIL-6 , ΔAGEs , and ΔbaPWV ; and positively correlated with ΔNO , ΔEPA , ΔEAA , ΔEMA , and ΔETF , ΔCRP , ΔTNF-α , and ΔIL-6 ; and negatively correlated with ΔEPCs , ΔEPA , ΔEAA , ΔEMA , and ΔETF  increased significantly in exendin-4-treated diabetic rats [Previous studies discovered that treatment with exenatide, but not with liraglutide, was able to inhibit the apoptosis of EPCs and significantly increase the number of circulating EPCs, possibly through an antioxidative/anti-inflammatory effect , 46. In tic rats . It was tic rats . Anothertic rats . At prestic rats , which ctic rats , and redtic rats . Persisttic rats . Our stutic rats . Anothertic rats . HoweverThe main shortcomings of this study are as follows: (1) the study has a small sample size and a short observation time. At the same time, it is unable to confirm the causal relationship between the changes in the number and function of EPCs and their cardiovascular benefits. Therefore, the findings need to be confirmed by prospective cohort follow-up studies. (2) Most of the patients included in this study are overweight or obese T2DM patients without ASCVD. Therefore, it is necessary to further explore the effect of dulaglutide on peripheral blood EPCs and arterial elasticity in non-obese T2DM patients or T2DM patients with ASCVD. (3) Reactive hyperaemia index (RHI) and flow-mediated vasodilation (FDM) are valuable indexes to evaluate vascular endothelial function and predict the prognosis of cardiovascular disease . Due to This study found that dulaglutide can increase the number and function of peripheral blood EPCs in patients with T2DM and improve arterial elasticity. This effect may be related to weight loss, inflammation reduction, and elevated NO levels, suggesting that the regulation of EPCs and the improvement of cardiovascular risk factors may be a mechanism of cardiovascular protection of dulaglutide.


It has been observed that intravenous iron administration may suppress endogenous production of erythropoietin (EPO). We postulate that this effect may be mediated by increased FGF-23 secretion.To evaluate the short-term effect of intravenous iron sucrose administration on endogenous EPO secretion in patients with chronic kidney disease (CKD).The cohort comprised 35 nondialysis patients with CKD stages 3–5. All received 100 mg of intravenous iron (III)-hydroxide sucrose complex daily for five consecutive days. Plasma EPO, iFGF-23, cFGF-23, PTH, bone alkaline phosphatase (BAP), phosphorus (PO4), calcium (Ca), and high-sensitive C-reactive protein (CRP) were measured before, and two hours after, the first and third iron infusions, and after completing iron therapy.p = 0.0003) and before the third dose (p = 0.0006) . Conversely, plasma iFGF-23 was significantly higher before the third dose  and after the course of treatment  compared to pretreatment value . cFGF-23 concentration was significantly lower than baseline after the first iron dose  and after treatment . No significant linear correlation was found between changes in plasma EPO and FGF-23.EPO concentration at the end of iron treatment was significantly lower than two hours after the first iron infusion (Although intravenous iron therapy causes parallel increase of FGF-23 and supression of endogenous EPO, these two effects seem to be independent. The most common long-term complications of chronic kidney disease (CKD) are anemia and mineral metabolism disorders . Both ofThe two main causes of renal anemia are relative erythropoietin deficiency and concomitant functional iron deficiency. Hence, for more than 30 years, the correction of iron metabolism disorders has formed the basis of renal anemia treatment by using intravenous iron preparations administered with agents that stimulate erythropoiesis . The repeated measures ANOVA or Friedman ANOVA were used for comparing multiple dependent groups, with subsequent p = 0.0003) and before the third iron dose (p = 0.0006) . All plasma EPO values assessed during the study are shown in The plasma EPO concentration was significantly lower at the end of the iron treatment than two hours after the first iron infusion (p = 0.025) and at the end of the treatment  compared to the pretreatment value . cFGF-23 concentration decreased significantly after the first iron dose  and after treatment completion  vs. baseline (p = 0.025). The changes of FGF-23 concentrations during the study are shown in Conversely, plasma iFGF-23 increased significantly before the third dose  during the study from baseline to day 6 . Nor were any observed for plasma EPO and FGF-23 changes in the first (baseline vs. 2 h after iron infusion on day 1) and the third day (before vs. 2 h after iron infusion on day 3) of the treatment.Regarding the individual data, in 16 of the 35 patients (45.7%), the increase of iFGF-23 concentration was accompanied by a decrease of EPO concentration.A positive, significant linear correlation was found between the changes in iFGF-23 and cFGF-23 on the first day of treatment (before treatment vs. 2 h after iron infusion on day 1). However, this effect was not observed on the third day (before vs. 2 h after iron infusion on day 3) nor throughout the treatment period (baseline vs. day 6), as presented in The changes in EPO (baseline vs. day 6) correlated significantly with baseline ferritin concentration .Moreover, concentrations of calcium, phosphate, PTH and BAP at the different time points of the study are shown in The main finding of the study was that administration of iron hydroxide sucrose complex IV infusion in non-dialysis CKD patients led to a parallel increase of plasma iFGF23 and a decrease of endogenous erythropoietin concentration.The links between endogenous erythropoietin production and mineral metabolism have not been thoroughly explored. However, in an experimental study, Coe et al.  found thThese findings suggest that a link exists between FGF23 secretion and renal anemia, independent of the severity of disturbances of other markers of mineral metabolism. In addition, some changes in mineral metabolism were observed in the CKD patients; for example, an increase in cFGF23 increase was noted during iron infusion, followed by a decrease in serum erythropoietin concentration.Although many studies have investigated the role of the phosphatonin FGF-23 in the pathogenesis of CKD, only a few have assessed its possible contribution to the development of renal anemia. However, a large-scale prospective cohort study found that high serum FGF23 levels were associated with an increased risk of anemia in patients with non-dialysis CKD .One of the considered theories was that inflammation may be one of the mediators of these changes. Interestingly, David et al. found that chronic inflammation increased biologically active iFGF23 levels  and mighAlthough the role of FGF-23 has been thoroughly investigated in the last two decades, the laboratory method of serum FGF-23 measurement remains a subject of controversy . That maAnother important fact was that, in our study blood was taken in the morning each day to avoid a potential influence of diurnal fluctuations in serum FGF23 and EPO levels . In addiIt was decided to only include patients with moderate or severe renal impairment who were not yet on dialysis. While FGF-23 plasma concentration always increases in the early stages of kidney disease, patients with end-stage kidney disease who have started hemodialysis demonstrated a much more pronounded increase in plasma FGF-23 than expected for the degree of kidney dysfunction. Therefore, the analysis of such data would have been significantly impaired .In our study group, the highest increase of FGF23 concentration was observed after the first three days of the treatment, which was consistent with the results of previous studies that showed the strongest effect on mineral metabolism to occur up to 72 h after the commencement of iron administration .As mentioned above, iron supplementation alone can induce an inflammatory response that may impair endogenous erythropoietin production. The presence of low-grade inflammation in most CKD patients could interfere with this effect. Therefore, patients with greatly increased CRP at baseline, which suggested acute inflammation, were excluded from the study .In addition to the presence of an inflammatory state, the type of iron preparation may also matter, since previous studies indicated that the chemical structure of the iron compound used for iv therapy might influence treatment-induced changes of mineral metabolism and probably secondary epo changes ,22. It wAnother important fact was that parallel changes in FGF-23 and EPO concentration were observed during the study; however, unlike animal studies, our results were not significant . Similarin vivo. The findings indicate that both cFGF23 and iFGF23 increased in four patients after EPO administration, but no such effect was observed in patients who underwent kidney transplantation. In that group, higher cFGF23 concentration was noted in those with higher serum EPO concentration, and this relationship was independent of graft function [A noteworthy study examined whether exogenous EPO stimulates FGF23 function . Many stfunction ,26,27,28However, studies based on FGF23-knockout mice or mice injected with iFGF23-blocking peptide resulted in increased erythropoiesis, reduced erythroid cell apoptosis and elevated renal and bone marrow erythropoietin mRNA expression with increased levels of circulating erythropoietin .An association has found between FGF23 and erythropoiesis in animal studies; however, this was suppressed at higher FGF-23 concentrations. In addition, all mentioned relationships appeared to be bi-directional, since elevated FGF-23 may reduce bone marrow EPO expression, and EPO may promote FGF-23 transcription in turn ,30. The In our study we were not able to find any significant correlation between EPO and FGF-23 changes during the study period. No correlation was observed regarding changes in iFGF nor cFGF; however, by analyzing the individual data, it was found that in about half of the patients, the increase in iFGF-23 concentration was accompanied by a parallel decrease in EPO concentration.The duration of iron therapy in the present study was six days, which seemed to be sufficient to explore the potential effect of an increased FGF23 concentration on endogenous EPO production. However, the changes in EPO and stimulation of erythropoiesis appear to be slow-acting processes .Our study has several limitations. The number of patients was low; however, it should be noted that there have only a scarce evidence coming from experimental study in this field ,29. As sIn conclusion, intravenous iron administration significantly affects mineral metabolism in non-dialysis CKD patients, but may also independently suppress the secretion of endogenous erythropoietin. Our findings may have implications for the diagnosis and treatment of renal anemia.