Chronic kidney disease (CKD) and cardiovascular complications are the leading causes of death in type 2 diabetes mellitus. Apart from the standard therapy, which includes angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), lipid-lowering medication, and anti-platelet therapy, the new group of drugs termed the 'sodium-glucose co-transporter-2 (SGLT2) inhibitors' have shown promising results in managing complications arising from the cardiovascular and renal systems in diabetics. This article attempts to highlight the role and mechanism of action of this class of drugs.  We reviewed 127 articles and analyses of randomized controlled trials using several drugs in the SGLT2 inhibitor family  over the past five years, out of which 58 met the criteria and aim of the study. These articles were retrieved from PubMed, Google Scholar, and Medline data sources and assessed for quality using the assessment of multiple systematic reviews (AMSTAR) checklist and Cochrane risk-of-bias tool. Results from the review showed significant benefits in reducing progressive renal decline, blood pressure control, heart failure hospitalization, death from renal or cardiovascular complications, myocardial infarction, and stroke. This benefit is also seen in non-diabetic patients, hence postulating that these effects may not be solely due to glycemic control. There are several mechanisms with which it achieves this benefit with the most significant being its role on intraglomerular pressure. Other pathways include blood pressure control, natriuresis, ventricular remodeling, erythropoiesis, lipid metabolism, plasma volume, and electrolyte imbalance.  It is clear that the role of SGLT2 inhibitors isn’t limited to glycemic control and they can achieve a wide array of functions by affecting different systems. More studies need to be done to completely understand this medication to improve the quality of life in diabetic and non-diabetic patients living with CKD and cardiovascular complications. The pharmacokinetics of this drug could also help set the basis for newer medications. Diabetes is a life-long disease that affects millions of people from across the globe. Roughly 422 million people were living with diabetes in 2014, which is almost a three-fold rise from figures in 1980 . This efDespite the use of renin-angiotensin inhibitors (e.g. angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB)), lipid-lowering and anti-platelet drugs, which are the standard therapy in managing these diseases, mortality remains high and it is clear that intensive research needs to be done to meet up with the demands of handling these obstacles. Sodium-glucose co-transporter-2 (SGLT2) inhibitors are the latest group of medications approved for managing diabetes, following documented benefits in several trials. Recent studies have shown significant effects in achieving glycemic control, reducing renal and cardiovascular complications. In some common cardiovascular outcome trials (CVOTs) such as the dapagliflozin effect on cardiovascular events led by the 'Thrombolysis in Myocardial Infarction' study group (DECLARE-TIMI 58), empagliflozin cardiovascular outcome event trial in Type 2 diabetes mellitus patients removing excess glucose (EMPA-REG), and the canagliflozin cardiovascular assessment study (CANVAS), SGLT2 inhibitors showed protective cardio-renal capabilities in diabetic patients with heart failure, CKD, and cardiovascular risk factors -7. More The mechanisms by which these effects on the cardio-renal system are achieved are not quite understood. In the renal system, some theories postulate the benefits are directly linked to its role in reducing intraglomerular pressure. While in the cardiac system, it is thought to be due to its action on cardiac progenitor cells, arterial stiffness, hematocrit levels, fluid, and electrolyte balance.  A comprehensive review of the effect and actions of the SGLT2 inhibitors on the cardio-renal system is important to effectively manage these complications and reduce mortality. In this paper, we aim to analyze the effects of this class of drugs on these systems as well as to provide a thorough review of its mechanism of action.  A better understanding of this process will give us more insight into achieving maximum success with this class of drugs and also set a benchmark for newer medications. Effect of SGLT2 inhibitors on the renal systemDiabetes causes a significant percentage of CKD, a condition that has affected millions of people worldwide . ManaginBlood pressure control is known to significantly reduce renal decline and, for a while, the ARBs and the ACEi were the only class of drugs that slowed down renal decline in diabetics with CKD. This study aims to highlight the significant effects of SGLT-2 inhibitors and attempts to understand their mechanism of action. Effects on Intraglomerular PressureIn the canagliflozin and renal events in diabetes with established nephropathy clinical evaluation (CREDENCE) trial, i.e., estimated GFR of 30 to <90ml/min/1.73m2 or albuminuria clinical evaluation, that was aborted early after the primary endpoints were reached, the SGLT2 inhibitors were effective in delaying the progression of CKD and reducing albuminuria. There was a 30% reduction in the risk of ESRD, doubling of creatinine, and death from renal or cardiovascular pathways . SeveralThe juxtaglomerular apparatus (JGA) is a segment of the nephron that regulates systemic blood pressure and comprises the juxtaglomerular cells, macula densa , and lacis cells . SGLT-2 Figure Effects on Homeostasis Its role on plasma volume is primarily via osmotic diuresis, which leads to blood pressure reduction, limiting further renal and cardiovascular damage. It has been postulated to also affect serum osmolality, particularly via sodium metabolism with resultant effects on the renin-angiotensin mechanism. Some studies showed that using empagliflozin 25mg was associated with increased urinary glucose excretion, transient natriuresis, and urine volume with no significant change in renin-angiotensin system . In patiWorthy of note is that single and multiple administrations of tofogliflozin achieved the same effect across various ranges of renal impairment, so dose titrations are not necessary ,23, hencEffect on Erythropoiesis One of the major problems associated with CKD is anemia. The presence of anemia complicates the clinical scenario and worsens the prognosis. An analysis of the CREDENCE trial by Oshima et.al. noted that the results of 'anemia outcome or the initiation of anemic treatment ' was lower in the canagliflozin arm than the placebo group. This reduces the need for frequent blood transfusions and the complications associated with this procedure, further reducing hospital visits, emergencies, and improving survival outcomes in these patients.  From the above studies, the SGLT2 inhibitors show increasing efficacy in patients with declining renal function. This appears to be independent of glycemic control, hence, its possible use in all patients with CKD. The lower limit of estimated GFR used in most studies was between 25-30ml/min/1.73m2 and more trials are being done to establish their role in lower estimated GFR levels and ESRD. There are lots of possible pathways that explain its mechanism of action but what is prominent across most studies are their effects on intra-glomerular pressure and effective glycemic control with a very low risk of hypoglycemia. Worthy of note with this class of drugs is their role in improving erythropoiesis, which translates to better outcomes and mortality in these patients. Some studies show a single dose recommendation with tofogliflozin achieves a similar effect ,22, HoweIn the CREDENCE trial by Cannot et al., the study involved canagliflozin in a double-blinded, randomized controlled trial using a total no. Of 4401 patients, 99.1% completed the trial, quality assessment using the Cochrane risk-of-bias tool was 93.7% in comparison to a double-blinded randomized control trial with dapagliflozin by Heerspink et al. involving 4304 patients of which 99.7% completed the study, quality assessment using CRBT was 87.5%. Although both studies had primary outcomes of ESRD and death from renal or cardiovascular causes, Heerspink et al. was also noted to have included a sustained decline in estimated GFR of at least 50% as part of its primary outcome. In post hoc analysis of the CREDENCE trial by Jardine et al., quality assessment using AMSTAR checklist was 78.5% while the quality assessment of the CANVAS trial by Neuen et al. using the same AMSTAR checklist was 82.1%. Effects of SGLT-2 inhibitors on the cardiovascular systemCardiovascular complications are the leading cause of death from diabetes. They further worsen other pre-existing and renal co-morbidities that are usually present in this group of patients. There is a wide range of cardiovascular complications associated with diabetes that include but are not limited to death, stroke, coronary artery disease, myocardial infarction, and heart failure. The burden of these complications on the patient and society is so immense that adequate interventions have to be formulated to deal with these problems. Several drugs are being used to help curtail these health conditions such as lipid-lowering drugs, antiplatelet therapy, and most recently the SGLT 2 inhibitors, which were originally used for glycemic control in diabetic patients but have shown significant effects in managing some of these complications, directly and indirectly. These benefits have also been noted to extend to the non-diabetic population. Effect on Blood pressure and Heart failure The inhibition of the sodium-glucose co-transporter in the proximal tubule promotes osmotic diuresis which decreases plasma volume, thereby reducing preload and ventricular strain. Since these parameters are significant factors in the pathophysiology of heart failure, it is a possible explanation for the benefits seen in these patients. SGLT2 inhibitors are also known to decrease systolic blood pressure through the same mechanism, further limiting the stress on the myocardium.  Similarly, in the CVOTs using empagliflozin (EMPA-REG) and canagliflozin (CANVAS), the risk of a three-point major adverse cardiovascular event (MACE); which includes cardiovascular death, non-fatal stroke, non-fatal myocardial infarction, was significantly reduced by 14% in the drug arm versus the placebo. Both studies involved Type 2 diabetes mellitus patients who had established CVD, while the CANVAS study involved patients with CVD risk factors. The DECLARE-TIMI 58 trial using dapagliflozin also showed a reduction in the 3-point MACE with greater effects in the population with previous myocardial infarction -15. MetaEffect on Myocardium  In the post hoc analysis of the EMPA-REG trial by Inzucchi et al., the reduction in cardiovascular deaths in patients receiving SGLT2 inhibitors occurred early, and as such it is unlikely that the primary mechanism by which it achieved this short-term advantage is via its role on atherogenesis . A betteIn the effects of empagliflozin on cardiac structure in patients with type 2 diabetes (EMPA-HEART) study, which was a randomized controlled trial using empagliflozin involving patients with type 2 diabetes mellitus and stable coronary artery disease, with a significant number with heart failure, there was a reduction in left ventricular mass index over a six-month period -30. WhatEffect on Atherogenesis In an attempt to fully understand the role of this drug on the atherosclerotic pathway, Katami et al. attempted to study the effect of tofogliflozin on the progression of carotid atherosclerosis. In the prospective randomized study, Type 2 diabetic patients with no apparent CVD history were placed on either tofogliflozin or placebo, carotid atherosclerosis was assessed using carotid intima-media thickness (IMT). Results showed an increase in (high-density lipoprotein) HDL-c with no apparent change in carotid IMT between the two groups . Apart fIn a double-blinded randomized controlled study conducted in 2019, patients with type 2 diabetes mellitus and a history of coronary artery disease who received empagliflozin showed a reduction in cardiovascular death by 48%, all-cause mortality by 43%, and heart failure hospitalization by 50% . In patiConcerns have been raised about the effect of these drugs when used in combination with other anti-glycemic medications, particularly as it affects glomerular filtration. However, Ikonomidis et al. showed that there was a synergistic effect in patients receiving other drugs in combination with SGLT2 inhibitors , these mFrom the review of the studies, it is clear that SGLT2 inhibitors have a pronounced effect on the cardiovascular system, particularly in those with already established CVD. It has been shown to reduce the risk of cardiovascular death, myocardial infarction, stroke, heart failure hospitalization, and blood pressure management. It achieves this possibly due to its effect on plasma volume, via natriuresis, leading to a reduction in the preload, which causes lowering of the blood pressure, but there are not enough studies on its role in serum osmolality and electrolyte balance. Other studies have highlighted a possible role in myocardial remodeling and erythropoiesis, which calls for its use in heart failure and acute coronary syndromes, although in this regard, more research needs to be done. Another possible route of action on the cardiovascular system is through an increase in HDL levels, which is associated with good cardiovascular outcomes. A synergistic effect has also been noted when this class of drugs is given in combination with other therapies. In the effect of sotagliflozin on cardiovascular and renal events in patients with type 2 diabetes and moderate renal impairment who are at cardiovascular risk (SCORED) trial by Bhatt et al. Accessing the efficacy of sotagliflozin in type 2 diabetes mellitus with CKD. It involved 10,584 patients (5292 in the sotagliflozin arm). The primary end-point was deaths from cardiovascular causes, hospitalization for heart failure, and urgent visits for heart failure. The estimated GFR of the participants was between 25-60 ml/min/1.73m2. Meanwhile, the CREDENCE trial using canagliflozin, involved 4401 patients with type 2 diabetes mellitus and CKD with cardiovascular primary end-point of cardiovascular death, non-fatal myocardial infarction or stroke, and hospitalization for heart failure, while the estimated GFR of the study group ranged between 30 to < 90ml/min/1.73m2. The post hoc analysis by Davies et al. involving canagliflozin used 2313 patients with varying cardiovascular risk factors while the EMPA-REG trial involved 7020 study groups with varying cardiovascular risk factors .LimitationsInclusion criteria included randomized controlled trials, review articles, and publications done in the past five years. Only three databases  were used while reviewing articles. This article did not comprehensively review studies done in certain populations like Africans, Asians, and Middle Easterners.SGLT2 inhibitors have shown to be effective in reducing renal and cardiovascular complications. This article aims to understand these benefits and their mechanism of action. It is been noted that renal decline and cardiovascular complications are significantly reduced in diabetes as well as non-diabetics. Besides glycemic control, the effect on intraglomerular pressure and plasma volume are more obvious pathways by which these drugs work in both groups. Other more probable pathways include the effects on erythropoiesis, natriuresis, ventricular re-modeling, electrolyte, and lipid balance. A better understanding of the action of this class of drugs will help to direct the proper use to achieve maximum potential in high-risk patients, while also reducing mortality, morbidity, and side effects. The benefits of these drugs are independent of glycemic control as seen in CKD patients without diabetes as well as its effects on the myocardium, therefore, more randomized clinical trials need to be done in the non-diabetic population. This could be potentially groundbreaking and perhaps offer more explanation to its pharmacokinetics.


The circadian BP profile (dipper versus non-dipper pattern) did reach neither statistical significance nor influence the odds ratio of those inflammatory markers for HMOD. We found that differences in some inflammatory markers between patients with and without HMOD were not explained by a different circadian BP profile.We aimed to explore the influence that the circadian blood pressure (BP) profile could exert on the correlation between some inflammatory markers and hypertension-mediated organ damage (HMOD). This was a cross-sectional study that included patients with primary arterial hypertension older than 18 years old. We included some parameters of 24 h ambulatory blood pressure monitoring collection and several inflammatory markers, as follows: platelet count (PTC), erythrocyte sedimentation rate (ESR), ultrasensitive C-reactive-protein, ferritin, fibrinogen, and uric acid. Myocardial hypertrophy, albuminuria, carotid intima-media thicknesses and ankle brachial index were assessed as HMOD presentations. Individuals were divided into two groups: patients with and without HMOD. We included 522 patients . Multivariate logistic regression analysis showed that male patients older than 50 years old with uric acid levels above 7 mg/dL, ESR higher than 20 mm/h, fibrinogen greater than 320 mg/dL and PTC lower than 275 × 10 Elevated blood pressure (BP) is a major global contributor to cardiovascular (CV) risk and premature death. Both office and out-of-office BP have an independent relationship with the onset of several CV events ,2.The presence of hypertension-mediated organ damage (HMOD) as a surrogate marker of inadequate BP control is related to an increased CV risk and mortality, and its prevention should be a therapeutic target. The literature also supports that 24-h ambulatory BP monitoring (ABPM) is a better predictor of HMOD and CV events than office BP ,4.Recent evidence suggests that inflammation, immunity and arterial hypertension (AHT) may be related to each other, triggering an unfavorable inflammatory status that might increase BP and lead to HMOD and CV disease. Furthermore, several studies revealed that the inflammatory status could play a role in abnormalities of BP circadian rhythm, while other studies suggest that BP circadian profile could be related to HMOD ,6,7.There is a large amount of evidence in AHT pointing to an association between some inflammatory markers and HMOD, highlighting the role of erythrocyte sedimentation rate (ESR), ultrasensitive C-reactive protein (US-CRP), uric acid, ferritin and fibrinogen. Furthermore, several blood count parameters including white blood cell (WBC) count, platelet count (PTC), and medium platelet volume (MPV) have become universally available markers of chronic low-grade inflammation, and multiple studies have pointed to an association between these markers and atherosclerosis, distortion of circadian BP profile and HMOD ,9,10.However, it is less well known whether a dipper and non-dipper BP profile could influence this correlation between some inflammatory markers and HMOD. Thus, the aim of our study was to explore the relationship between some inflammatory markers and HMOD, and to assess whether this correlation could be independent of the circadian BP profile.This was a cross-sectional study with a retrospective data analysis that was conducted at the Department of Internal Medicine (Hypertension and Cardiovascular Risk Unit) of the University Clinical Hospital of Santiago de Compostela . Patient recruitment and data collection took place between January 2008 and December 2014.The study included patients with primary AHT who were greater than 18 years old. Causes of secondary AHT were investigated in those patients with suggestive clinical findings according to recommendations proposed by the European Society of Cardiology (ESC) guidelines on AHT. Patients suffering from secondary AHT were not included .Individuals with coronary arterial or cerebrovascular disease, acute or chronic renal impairment, fever, malignancy, or hematological disease were excluded from the study. Patients with acute or chronic respiratory diseases including obesity hypoventilation syndrome and sleep apnea syndrome were also excluded.Suspected infection or any other inflammatory process was investigated on the basis of the anamnesis and physical examination. In case of clinical doubt, specific physical examinations and complementary tests were carried out. Patients suffering from any cause of acute or chronic inflammatory or infectious disease were not included.HMOD presentations were considered on the basis of definitions that were supported by the European Society of Cardiology (ESC) guidelines on AHT as follows: electrocardiogram (ECG) voltage criteria for left ventricle hypertrophy (LVH) by Sokolow–Lyon criterion; albuminuria estimated with the albumin:creatinine ratio (ACR) in early morning spot urine sample, ankle–brachial index (ABI) measured with an automated device (Microlife WatchBP Office ABI ©) and carotid intima-media thickness (IMT) quantified by carotid ultrasound .® device . Ambulatory BP was recorded every 20 min during the day (daytime: from 07:00 to 23:00) and every 30 min at night (night-time: from 23:00 to 7:00). The following indexes were available from the 24 h ABPM recordings: average systolic BP over 24 h (24-hSBP), average diastolic BP over 24 h (24-hDBP), average systolic BP during the day (dSBP), average diastolic BP during the day (dDBP), average systolic BP during the night (nSBP) and average diastolic BP during the night (nDBP), percentage of systolic BP fall during the night (SBPF), and percentage of diastolic BP fall during the night (DBPF). A non-dipper pattern was defined as a decrease in nSBP and/or nDBP < 10% compared with the average daytime values. A dipper pattern was defined as a decrease in nSBP and/or nDBP ≥ 10% and <20% compared with the average daytime values [Patients underwent 24 h ABPM using an oscillometric Space-Labs 90207e values .Quality controls were also performed to exclude poor 24 h ABPM data. Values of SBP < 70 or >250 mmHg, DBP < 40 or >150 mmHg, and heart rate (HR) < 40 or >150 bpm were excluded from the recording. The method was considered to be reliable if >70% of measurements were valid. Our study was conducted in accordance with the recommendations of the main international clinical practice guidelines on ABPM, and patients completed a diary about their sleep quality ,14.2, waist circumference (WC) measured above the iliac crests in cm, diabetes mellitus (DM), hyperlipidemia (HLP), antihypertensive treatment, and lipid lowering therapy. AHT and HLP were defined in accordance with ESC Clinical Practice Guidelines. DM was considered in accordance with the American Diabetes Association guidelines (ADA). WC was measured using the same standardized tape measure in all cases. Therapeutic compliance was evaluated with the Morisky–Green questionnaire [All patients were assessed for demographic characteristics (age and sex) and CV risk factors, including smoking status (non-smokers versus current or former smokers), alcohol intake (no consumption versus consumption of any amount), body mass index (BMI) with height: weight ratio in kg/mionnaire ,15,16.Blood samples were obtained at 08:00 following overnight fasting. The following analytical variables were collected: complete blood count and biochemistry parameters including fasting plasma glucose (FPG), creatinine, and uric acid, lipid profile , US-CRP, ESR, ferritin, and fibrinogen. On the basis of evidence supporting inflammation in the pathogenesis of AHT and a possible role of some previously noted parameters in its quantification, we selected PTC, ESR, fibrinogen, uric acid, US-CRP and ferritin as inflammatory markers ,10.As for HMOD quantification, the threshold for abnormality was set as considered by clinical practice guidelines: ECG LVH: Sv1 + Rv5 > 35 mm; carotid IMT > 0.9 mm; ABI < 0.9; and ACR ≥ 30 mg/g .2 association test [Variables of interest were collected in accordance with the information that was provided by our regional digital health records . Non-categorical predictive variables with clinical and/or statistical relevance were recoded into dichotomous ones to improve the efficiency of multivariate analysis and to conduct interaction–confusion studies. The cut-off points for categories were calculated as the value of the independent variable that best classified patients in the group with and without HMOD using the chiion test .Taking into account the 24 h ABPM parameters and definitions previously discussed, the circadian BP profile was expressed as a qualitative variable called presence of a non-dipper profile (No/Yes) .As the rationale of the study was to perform a global assessment of differences in some inflammatory markers between patients with and without HMOD and taking into account the existence of missing data in some HMOD presentations, we recoded all HMOD presentations as a qualitative variable which was the presence or absence of any type of HMOD. The sample size was determined by the total number of recruited patients.www.clinicaltrials.gov (accessed on 21 February 2022), with identifier code NCT00295542) and it was approved by the Institutional Ethics Committee of the University Clinical Hospital of Santiago de Compostela. All subjects gave their informed consent for inclusion. The study was conducted in accordance with the Declaration of Helsinki.This study was included in the framework of the MAPEC project  and median with interquartile range (IQR), respectively. A chi-square test was used for categorical variables to test differences between groups. Results were shown as number (n) and percentage (%) of patients. For those variables with more than 5% of missing records, a missing value analysis was performed.Statistical analysis was performed using SPSS 20.0 statistical software . Univariate analysis was used to explore individual associations between some inflammatory markers and HMOD. Comparisons were made between patients with and without HMOD. The Kolmogorov–Smirnov test was used to determine whether continuous variables were normally distributed. Normally distributed variables were analyzed using the Student’s p-value of lower than 0.05 (p < 0.05) in the univariate analysis. Variables with p ≥ 0.20 were not shown. Results were expressed as the odds ratio (OR) and 95% confidence interval (95%CI) for HMOD. Statistical power was calculated as a function of the sample size, confidence level and a minimum effect size to be detected for the inflammatory markers evaluated in patients with HMOD. Finally, we assessed the performance of some inflammatory markers and clinical variables for HMOD with a model of receiver operating characteristics (ROC) curves. Results were provided as the area under curve (AUC) and 95% CI. Multivariate logistic regression analysis was used to assess the correlation between inflammatory markers and HMOD taking into account possible interaction and confounding phenomena between clinically relevant variables. The inclusion criterion for the variables was a p < 0.05). The most relevant results are shown in There were 522 patients (47% women) with a mean age of 54 years who were included in the study, and among them, 154 (29%) and 365 (69%) suffered from DM and HLP, respectively. A total of 232 (45%) patients showed a non-dipper BP profile while 211 (40%) individuals exhibited some type of HMOD. One out of three patients was a current or former smoker. There were clinical and statistical differences in age, sex, WC, presence of DM, HLP and a non-dipper profile between patients with and without HMOD (p < 0.05). We observed more than 10% of missing values in therapeutic compliance that were shown to be missing at random (data not shown). Most patients were compliant, and there was no difference in therapeutic adherence between groups. Renin–angiotensin–aldosterone system (RAAS) blockers were the most widely used group of drugs, and angiotensin II receptor blockers (ARBs) were the most frequent molecules  between patients with and without HMOD (olecules .p < 0.05). The results are shown in As for the office BP measurement, patients with HMOD had higher levels of SBP than the control group. The 24 h ABPM showed that patients with HMOD had lower levels of 24-hDBP and dDBP than the control group (p < 0.05). ESR, uric acid and ferritin levels were higher in patients with HMOD with a greater PTC in the control group (p < 0.05). There were also relevant differences in fibrinogen levels. There were more than 50% missing values for the US-CRP. Patients with HMOD had higher FPG and creatinine levels with lower total cholesterol (TC), low-density lipoprotein- cholesterol (LDL-C) and high-density lipoprotein- cholesterol (HDL-C) concentrations than individuals without HMOD (3/µL were associated with HMOD (p < 0.05). The results of the multivariate analysis are shown in After an adjustment by age, sex, smoking status, WC, DM, HLP, BP circadian profile, antihypertensive therapy and lipid-lowering drugs, the results of the multivariate logistic regression analysis showed that male hypertensive patients greater than 50 years old with uric acid levels above 7 mg/dL, ESR higher than 20 mm/h, fibrinogen greater than 320 mg/dL and PTC lower than 275 10Our study is one of the first studies that focus on the influence that the circadian BP profile and some other variables related to CV risk could exert on the correlation between some inflammatory markers and HMOD. The main results were as follows: (1) a nondipper BP profile and HMOD showed a prevalence of 45% and 40% respectively; (2) univariate analysis showed that patients with and without HMOD had relevant differences in age, sex, smoking status, WC, DM, HLP, circadian BP profile, antihypertensive therapy and lipid-lowering drugs; (3) multivariate analysis supported that PTC, ESR, fibrinogen and uric acid were correlated with HMOD independently of the circadian BP profile and some other classical variables related to CV risk.AHT may lead to deleterious structural and functional changes in heart, blood vessels, brain, kidney, retina, and other target organs. Subclinical HMOD is important as an intermediate stage in the continuum of CV disease and some inflammatory mechanisms seem to be crucial in the development of some AHT-related abnormalities such as HMOD and alterations in BP circadian profile ,19.There seems to be a dual interaction between inflammatory markers and HMOD but it remains unclear which one is more of a cause than a consequence. Several factors could be related to a pro-inflammatory environment and HMOD promoting this relationship. However, the vast majority of elements involved, the function they would play and the weight they would have in HMOD still represent a gap in evidence ,21.It is well known that HMOD is associated with endothelial dysfunction and an increasing number of studies have shown that some inflammatory markers are directly or indirectly associated with the presence of endothelial dysfunction through physical or chemical mechanisms, highlighting the role of platelets, ESR, fibrinogen and uric acid ,23,24.Uric acid levels are invariably associated with higher atherosclerosis burden and CV disease. The enzyme xanthine oxidoreductase has two dual isoforms. In situations of vascular damage such as AHT or myocardial ischemia the predominant isoform is xanthine oxidase which induces the formation of reactive oxygen species (ROS) contributing to endothelial dysfunction ,26.Some causes of organ injury are known to induce an increase in fibrinogen proteolysis leading to the release of fibrinogen-degradation products (FDPs). FDPs are able to interact with vascular endothelium enhancing an increase in vascular permeability. Inflamed endothelial cells can also call for circulating activated platelets, leading to platelet adhesion to the vascular wall. Upon adhesion, activated platelets release many pro-inflammatory cytokines and chemokines ,28,29,30Some of the factors that could be involved in a higher uric acid and fibrinogen levels observed in patients with HMOD could also be related to a pro-inflammatory internal milieu leading to increased levels of some acute phase molecules that would elevate ESR as a known nonspecific marker of inflammation ,32.The literature also supports the existence of differences in inflammatory markers depending on age, sex, toxic habits, lipid profile, diabetes mellitus or abnormalities of the circadian BP profile, among others. Moreover, patients with HMOD are often individuals who share multiple CV risk factors, so one might suspect that the differences in levels of certain inflammatory markers between patients with and without HMOD could be attributable to clinical differences between groups .However, our study suggests that the individual weight of some classical variables associated with HMOD on the levels of certain inflammatory markers could be negligible. In particular, the inclusion of the circadian BP profile within the model has not modified the correlations previously showed for PTC, ESR, fibrinogen and uric acid. These findings may support that multiple not-sufficient, not-necessary and also not-known factors could be behind the differences in some inflammatory markers between patients with and without HMOD.This was a cross-sectional study of real clinical practice in which we had to take into account the possibility of biases that were related to the design. Our study was carried out in Caucasian patients from the northwest region of Spain  who exhibited similar features than people from the western European countries. Therefore, results must be interpreted with caution when applying them to other populations, races or ethnicities.The consideration of only two circadian BP profiles (dipper and non-dipper) is a limitation to be highlighted as it leaves out patients with extreme dipper or riser BP profiles that, although they represent a minority, could provide different data and influence the results. .It is widely known that the use of antihypertensive and lipid-lowering drugs and the presence of DM are more prevalent in patients with HMOD and in those individuals with abnormalities of the circadian BP profile. In this regard, our study also yielded substantial differences between groups . Therefore, despite the efforts to manage confounders at the analysis phase, it is possible that the differences observed in inflammatory markers between patients with and without HMOD as well as the apparent better control of some diastolic BP indexes that was observed in patients with HMOD could be partially due to an unbalanced distribution of some relevant variables between groups.The high number of missing values for US-CRP may have limited the existence of differences between patients with and without HMOD as supported by other studies ,37.Some types of HMOD were not evaluated, highlighting the presence of retinopathy or damage to the central nervous system. The design of a global model for HMOD lacks the explanatory power that individual assessment of the different types of HMOD presentation would have. However, we believe that one of the strengths of this study was the high statistical power achieved (close to 90%) which allow us to support the results in a more robust way. This study represents a first approximation that would need to be corroborated by better quality designs.We found that differences in some inflammatory markers between patients with and without HMOD appear to be multifactorial and would not be explained only by individual CV risk factors including an abnormal circadian BP profile. The authors suggest that assessment of some inflammatory markers and blood count parameters should be included as a part of the evaluation and follow-up of hypertensive patients as an additional tool in the early suspicion of HMOD.


Hypertension has been a global public health problem. Qigong as a complementary and alternative therapy is often used to reduce blood pressure. The aim of this meta-analysis was to investigate the effects of Qigong on blood pressure in hypertensive patients.  Six electronic resource databases were searched from inception to January 2019, and randomized controlled trials of Qigong on hypertension were retrieved. Meta-analysis was conducted according to the guidelines of the Cochrane Collaboration, and Review Manager 5.3 was applied. Two researchers independently identified articles to include based on inclusion/exclusion criteria, data extraction, and quality evaluation. P < 0.00001) and diastolic blood pressure , P < 0.00001). There is, however, no significant difference between Qigong and other aerobic exercises in reducing blood pressure.  Fourteen studies, with 829 individuals, were included. The meta-analysis demonstrates that, compared with no exercise, Qigong has significant positive effects on systolic blood pressure ,  Qigong can effectively reduce blood pressure levels. Longer-term engagement in the practice has an even better effect in hypertension patients. However, the conclusion of this study still needs to be verified by more high-quality studies. Hypertension is a global public health problem and an essential preventable factor of cardiovascular diseases , 2. AccoModern medical research suggests that appropriate physical activity can effectively control and prevent the occurrence of hypertension and its complications . StudiesQigong is a traditional fitness method that originated from ancient China . It has The aim of this meta-analysis was to investigate the effects of Qigong on hypertension and explore the dose-response relations between quantity of motion in Qigong exercise amount and blood pressure level of hypertension patients using meta-analysis.This study mainly contains a meta-analysis of all randomized controlled trials involving Qigong to treat hypertension published in English or Chinese. The review is carried out under the instructions of the Cochrane Collaboration .This study searched the Cochrane Library, China Science and Technology Journal Database (CQVIP), MEDLINE via PubMed, Web of Science, Wan Fang Data, and China National Knowledge Infrastructure (CNKI), to find randomized controlled trials exploring Qigong's effects on hypertension, and retrieved data to January 2019. Besides, references to studies are also considered to prevent omission. There are two kinds of search terms, namely, target (hypertension) search term and intervention (Qigong) search term, which were slightly adjusted according to the specific database. A combination of subject search and free search was used in all retrieval. Seven presearches are used to facilitate search strategies. Certain search terms include Qigong, Baduanjin, Wuqinxi, high blood pressure, hypertension, blood pressure, systolic blood pressure (SBP), and diastolic blood pressure (DBP).(1) Studies in Chinese and English. (2) The randomized controlled trial  shall be included. (3) With no restrictions on gender or age of subjects with hypertension. (4) Blood pressure (systolic and diastolic) was measured. (5) Qigong was tested as the main intervention compared to any other control. (6) The major intervention in the control group must be one of no exercise  or other aerobic exercises  or resistance exercises. (7) Patients without serious hypertension-related complications.(1) Nonrandomized controlled trials. (2) Studies that did not include data of indicators (systolic blood pressure and diastolic blood pressure) to be discussed in this study. (3) The major intervention in the control group was not one of no exercise  or other aerobic exercises  or resistance exercises. (4) The major intervention in the experimental group was not Qigong. (5) Patients with serious hypertension-related complications.Databases such as The Cochrane Library, VIP, MEDLINE via PubMed, Web of Science, Wan Fang Data, and CNKI were retrieved according to the inclusion and exclusion criteria and the effects of fitness Qigong on blood pressure. 924 potentially relevant documents were found in the searched database, and 342 documents were retained after the duplication of the literature was removed. Among these, 305 were deleted by reading titles and abstracts, and 23 were excluded after reading the full text according to the inclusion criteria. Finally, a total of 14 trials were included –31, inclDuring the process, two researchers did independently and if disagreements arose, the third person was involved to analyze and decide whether to include and exclude. Data extracted include information of the first author, publication date, past published journals, paper title, intervention measures of experimental group and control group, intervention period, number of experimental group and control group, and info of patients (age and gender). Hypertension indicators shall include systolic and diastolic blood pressure.During the data extraction process, the quality of the included studies was evaluated using the Cochrane Collaboration's tool for assessing risk of bias. Evidence from studies was classified as having a low, unclear, and high risk of bias. This process was conducted independently by two researchers on quality assessment and resolves differences by soliciting the opinions of a third person.Outcomes of each included study are shown in χ2. Statistical homogeneity between the results of each study indicated that when P > 0.1 and I2 <50%, the fixed effect model was adopted. When heterogeneity showed P > 0.1, I2 >50%, heterogeneity was analyzed by subgroup analysis. If there was no heterogeneity between subgroups, a fixed effect model was used. When statistical heterogeneity existed among subgroups in the included studies, a random effect model was used for meta-analysis. If there was too much heterogeneity between groups, descriptive analysis was performed. Sensitivity analysis was applied if necessary. Possible publication bias was assessed using funnel plot and Egger's test. The funnel plots were constructed based on the logarithm of the effect sizes against the standard error of the effect sizes for studies included in the meta-analyses. The trim and fill method was applied to correct the effect of possible bias. Mean differences (MD) for each study were calculated by subtracting the score difference in the control group (systolic blood pressure and diastolic blood pressure) from the score difference in the intervention group. Negative values were indicative of improvements (reductions) in systolic blood pressure or diastolic blood pressure. In addition, 95% confidence intervals (CI) were calculated.Review Manager 5.3  and Stata 14.0  software were used for meta-analysis. The heterogeneity test between the results of included studies was ∗ Qigong exercise days per week ∗ total of Qigong exercise weeks .In order to reveal a dose-response relationship between Qigong and blood pressure lowering among patients with hypertension, this study compared the amount of exercise of people doing Qigong and that of inactive people and conducted stratified subgroup analysis. Because Qigong can be considered as a kind of moderate-intensity aerobic exercise , in thisA total of 14 randomized controlled trials, with a total of 829 subjects, were included. The ages of these subjects were within 40.0–71.0 years, with a minimum follow-up time of 10 weeks and a maximum follow-up time of 1 year. All patients in intervention groups maintained routine medication and received Qigong intervention at the same time. 5 articles have adopted the Baduanjin –23, 27; (1) Qigong versus Nonexercise. n = 600) could be combined, but the data heterogeneity was relatively high. According to the subgroup analysis of the total amount of exercise, the heterogeneity of the superlarge exercise group was as high as 88%. By sensitivity analysis of the data, it can be inferred that the data of Yanfang Cai 2016 was the main source of heterogeneity in the superlarge exercise group. Accordingly, we excluded data from the studies and reported the data. Finally, data were collected from 10 studies (n = 487), and the results showed that systolic blood pressure in the Qigong group was lower than that in the nonexercise group, with statistically significant difference , P < 0.00001). With an exercise amount of 1–6000 minutes, the subgroup pooled effect size increased with the increase of total exercise amount. With exercise amount of 4501–6000 minutes, the subgroup pooled maximum effect size , P < 0.00001).(2) Qigong versus Other Aerobic Exercises. As shown in n = 229) [P=0.77).n = 229) , 24, 29 (1) Qigong versus Nonexercise. Initially, the data of 10 studies [n = 508) were collected, and the results showed that DSP in the Qigong group was lower than that in the control group, and the difference was statistically significant , P < 0.00001). Above 3000-minute exercise amount, the subgroup pooled showed statistically significant difference . With an exercise amount of 4501–6000 minutes, the subgroup pooled maximum effect size , P < 0.00001)  .(2) Qigong versus Other Aerobic Exercises. Data from 3 [n = 229) could be synthesized as shown in P=0.85).a from 3 , 24, 29 p=0.147). A trim and fill analysis showed that no study was missed or trimmed. Overall, there was no evidence of publication bias in this analysis.A funnel plot was used to analyze systolic blood pressure in the Qigong group and inactivity group. A total of 10 studies involving 487 subjects were included. These results indicate that the included studies were symmetrically distributed on both sides of the funnel plot . AnalysiThe diastolic blood pressure (DBP) was analyzed with funnel plots including 3 studies and 229 subjects. The results showed that the funnel plot included in the study was asymmetrically distributed on both sides, indicating a potential publication bias in the comparison of Qigong and other aerobic exercises .According to the results of this study, Qigong has a positive effect on the reduction of diastolic and systolic blood pressure indicators compared with no exercise in hypertension patients. This result is basically consistent with the results of three published studies on systematic evaluation and meta-analysis –14. As aFrom the perspective of modern sports medicine, based on the form of Qigong exercise and its exercise intensity, we conclude that it is one kind of regular and moderate intensity of aerobic exercises . In thisAt present, there are few pieces of research at home and abroad on whether there is a dose-effect relationship between exercise (including Qigong) and blood pressure level in hypertension patients. However, a study showed a linear dose-response relationship between blood pressure levels and exercise levels, with higher exercise levels associated with lower blood pressure levels . AccordiAccording to the meta-analysis results, the exercise amount of Qigong of 4501–6000 minutes has a better effect on the reduction of diastolic blood pressure and systolic blood pressure. Therefore, in order to better regulate the diastolic blood pressure and systolic blood pressure level, it is recommended to do 90–120 minutes of Qigong exercise every week for more than one year or 180–240 minutes of Qigong exercise every week for more than half a year. This recommended amount of exercise for Qigong is basically the same as 150 minutes of weekly aerobic exercise with moderate-intensity recommended in most guidelines of clinical practice .This study found that Qigong exercise is positive and effective in reducing hypertension. In patients with hypertension, Qigong exercise for 90–120 minutes per week for more than one year or 180–240 minutes per week for more than half a year is the better treatment for hypertension. It must be pointed out, however, that these are general recommendations. It is worth noting that Qigong is easier to learn and has fewer side effects than other treatment methods for hypertension (standard exercise and drugs) . EspeciaLimitations of this study shall also be taken into account. Firstly, limited by objective conditions, only MEDLINE via PubMed, The Cochrane Library, Web of Science, CNKI, Wan Fang Data, and VIP were applied, so potential omissions may occur; secondly, the quality of included papers was low and the random distribution method and blind method was not described; thirdly, our study did not use metaregression to adjust for confounding factors; fourth, due to the large heterogeneity of the included studies, only random effect model can be adopted, which will have a certain impact on the results; fifth, some confidence intervals (CI) that are too wide may not estimate precise.Qigong can effectively reduce blood pressure levels, and 90–120 minutes every week for more than one year or 180–240 minutes every week for more than half a year has a better effect in hypertension patients. Moreover, according to the subgroup analysis of the total Qigong exercise amount, there may be a dose-response relationship between Qigong exercise amount and blood pressure level in hypertension patients. However, the conclusion of this study still needs to be verified by more high-quality studies.


PCNT). Aside from its classic features, there are multiple associated medical complications, including a well-documented risk of neurovascular disease. Over the past several years, it has become apparent that additional vascular issues, as well as systemic hypertension and kidney disease may also be related to MOPDII. However, the frequency and extent of the vasculopathy was unclear. To help address this question, a vascular substudy was initiated within our Primordial Dwarfism Registry.Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) is the most common form of primordial dwarfism, caused by bialleic mutations in the pericentrin gene (Medical records from 47 individuals, living and deceased, ranging in age from 3 to 41years of age were interrogated for this purpose. Of the total group, 64% were diagnosed with moyamoya, intracranial aneurysms, or both. In general, the age at diagnosis for moyamoya was younger than aneurysms, but the risk for neurovascular disease was throughout the shortened lifespan. In addition to neurovascular disease, renal, coronary and external carotid artery involvement are documented. 43% of the total group was diagnosed with hypertension, and 17% had myocardial infarctions. A total of 32% of the entire cohort had some form of chronic kidney disease, with 4% of the total group necessitating a kidney transplant. In addition, 38% had diabetes/insulin resistance. Ages of diagnoses, treatment modalities employed, and location of vasculopathies were notated as available and applicable, as well as frequencies of other comorbidities.It is now clear that vascular disease in MOPDII is global and screening of the cardiac and renal vessels is warranted along with close monitoring of blood pressure. We recommend a blood pressure of 110/70mmHg as a starting point for an upper limit, especially if the individual has a history of neurovascular disease, chronic kidney disease and/or diabetes. Additionally, providers need to be at high alert for the possibility of myocardial infarctions in young adults with MOPDII, so that appropriate treatment can be initiated promptly in an acute situation. PCNT) gene [7Microcephalic osteodysplastic primordial dwarfism type II , first described by Majewski, Ranke, and Schinzel (1982) 2. MOPDII NT) gene , 6. AsidT) gene 7. There iT) gene 716.Care has changed dramatically over the past decade for individuals with this diagnosis, and has become more proactive than reactive in some domains, as associated medical conditions became known and screening for these issues could be initiated. With genetic testing now clinically available, a diagnosis can be quickly confirmed and recommended care guidelines put in place, to screen for neurovascular abnormalities, orthopedic manifestations, and insulin resistance . ApproprAs neurovascular screening by imaging began to be performed in this population, treatments could be initiated if moyamoya and/or aneurysms were identified, oftentimes before clinically apparent. As children became young adults and survived past these potentially life-limiting neurovascular concerns, new medical complications have emerged including: renal failure necessitating kidney transplantation and coronary artery disease leading to myocardial infarctions , 19, 20.To systematically ascertain the medical problems associated with MOPDII and other forms of microcephalic primordial dwarfism (MPD), a Primordial Dwarfism Registry was established in 2008 at the Alfred I. duPont Hospital for Children. The study has been approved by the hospitals ethics board, specifically Institutional Review Board protocol#: 83142. The registry collects retrospective medical records. To date, 128 patients with various forms of MPD have been enrolled via a written consent process. Fifty five of these individuals have a diagnosis of MOPDII.In 2018, we created a MOPDII Vascular Substudy for those specifically with a clinical and/or molecular diagnosis of MOPDII already within the Primordial Registry. Forty-two families/individuals were able to be re-contacted, and written consent was obtained from 40 families for this specific project; 1 had declined outright after the death of their child, and 1 could not complete the consent process. Of those consented, 6 partially and 24 fully completed a detailed questionnaire on this topic, online in REDCap. Information obtained from the questionnaire was used to document the medical journey of each, as well as acted as guidance for requesting specific medical records of interest, to obtain the most vetted relevant data possible.Of everyone enrolled in the Primordial Registry with MOPDII, 8 patients were removed from review  due to lack of sufficient medical records. Therefore, 47 individuals data was used for analysis, see Table It is worth noting that sometimes the answers to the questionnaire differed from medical records. For example, for some on a multitude of medications, the questionnaire answer was no to any medical issues, both when provided a list of possibilities and when allowed to enter the answer as free text. In these instances, we defaulted to medical records and past personal communication with the individuals.Additionally, it became apparent in reading reports that moyamoya is a somewhat subjective radiographic diagnosis, as neurosurgeons had differing opinions on the same imaging. However, once moyamoya was identified by at least one specialist, we notated it as such. There were some instances where a child had a documented ischemic stroke, but was not formally diagnosed with moyamoya until a later date. For the purposes of this analysis, in these instances we denoted the date of moyamoya diagnosis as the date of the ischemic stroke. We noted some discrepancy in aneurysm diagnosis as well. There were instances when an aneurysm was diagnosed, and in hindsight the neurosurgeon could visualize the subtle imaging changes, but the prior image report did not identify that finding. In these instances, we denoted the aneurysm diagnosis as the later date, once it was reported without ambiguity.Locations were tallied for not only those diagnosed as moyamoya, but also vessels designated as stenotic, narrow, or hypoplastic by brain MRA. The location of any aneurysms, as well as outpouchings also known or tiny aneurysms were included as well. When an individual had many or multiple aneurysms designated in their report, they were only counted as 1 for a particular location, since the exact number was unknown. When stenotic vasculature included multiple branches of an artery and/or different locations, then each branch was tallied with a 1. Additionally, some individuals were only noted to have moyamoya and/or aneurysms, with location unspecified.Also, some information was not categorizable, so unfortunately not all information could be included in the statistics. For example, a child with a history of both moyamoya and aneurysms was noted to have had neurosurgery in childhood according to parental questionnaire; as it was unknown if this was a moyamoya or aneurysm repair, this surgery was not tabulated.In order to determine survival probabilities, a KaplanMeier survival analysis was conducted using R (version 3.6.1), the survminer  and survPCNT . One individual had a clinical diagnosis of MOPDII with classic features and MOPDII comorbidities, but did not have molecular testing as he died before it was clinically available. The final two individuals did not have biallelic mutations identified, but absence of PCNT protein was observed in a research setting [As Table  setting .A KaplanMeier (KM) survival curve was constructed for this population; see Fig.In this cohort of 47 individuals, 47% n=22) were diagnosed with moyamoya  had aneurysms identified ; see Fig.Not everyone with MOPDII has one of these neurovascular diagnoses. There were 17 individuals (36%) diagnosed with both moyamoya and intracranial aneurysms, but 17 individuals (36%) with neither; Table In general, the age of diagnosis for moyamoya is at an earlier age than aneurysms. Aneurysmal risk appears to increase at a relatively steady rate throughout childhood, and continues into adulthood, whereas the moyamoya slope is much steeper prior to age 5 Fig.. About aTable Of the 47 total individuals, 17% (n=8) had premature myocardial infarctions . These included: 3 documented STEMI , 1 NSTEMI  and 4 with no medical details about their specific cardiac event available. Of the total eight individuals, three experienced more than one acute coronary syndrome event. One additional individual was diagnosed with coronary artery disease (CAD), but did not have a known history of a myocardial infarction.Of these individuals with CAD/MI, 78% (7/9) were managed with cardiac surgery/catheterizations; the others may have been, but all records were not available to us. These included four with stenting of coronary arteries, two catheterizations without stenting , and one with unknown details. Two individuals had more than one cardiac catheterization, and one individual necessitated coronary bypass surgery.Twenty eight percent (n=13) had a history of ASD, VSD or PFO beyond the newborn period, and one additional individual had multiple rhabdomyomas.Two percent (n=1) were diagnosed with renal artery stenosis; 7 others also had this suggested by renal ultrasound with Doppler, but subsequent MRA/CTA failed to confirm the diagnosis. In addition, 4% (n=2) were diagnosed with renal aneurysms (mean age of 10years); one had the aforementioned renal artery stenosis and went on to have partial infarct of a kidney, and the other individual subsequently had a kidney transplant. See Table Eight individuals have been diagnosed with chronic kidney disease, stage III or higher, at a mean age of 22.6years old. Seven additional individuals had record of CKD stage I, II, or unknown stage, to total 32% of the entire cohort with some form of chronic kidney disease. Two individuals underwent kidney transplants, at 23y7m and 21y2m of age.Thirteen percent (n=6) were noted to have nephrolithiasis , all of whom were on anti-hypertensive medications. One needed treatment by ureter stenting at 21years of age.Regarding structural differences, 28% of males (n=7) had accessory/duplicated renal arteries Fig.; interesBeyond that noted in the neurovasculature, renal and coronary vessels, there have been reports of other vascular issues for individuals with MOPDII. Specifically, the external carotid artery was identified as stenotic for 3 individuals Fig., and theAdditionally, the femoral artery has been a common location for insult, given the catheterizations needed for examination and treatment of associated medical concerns. This has occurred for 13% (n=6) of all individuals in our cohort. Three individuals were documented to have femoral artery occlusion after procedures which then necessitated fasciotomies and thrombectomies to treat; however, one went on to need patch and bypass, and after subsequent complications eventually lost the artery and full use of the leg. Another individual was found to have collapse of a superficial femoral artery, treated by bypass; later noted to have thrombosis with subsequent restenosis and revision. An additional individual was noted to have a femoral artery pseudoaneurysm, treated by thrombin injection. Lastly, yet another individual had focal severe stenosis identified in the common iliac artery, leading to stent placement, and subsequent in-stent restenosis.Forty three percent of individuals n=20) in this cohort had either diagnosed hypertension and/or were treated with anti-hypertensive medications. Another 6% (n=3) were diagnosed with borderline or pre-hypertension; this was the terminology found in their medical records to describe their elevated blood pressure. Among those diagnosed with hypertension and/or elevated blood pressure, the median age was 13years (range 036years old); see Table 0 in thisCriteria for diagnosing hypertension was not always consistent among the population. While some providers chose the convention of defining appropriate blood pressure based upon height percentile, others chose to utilize a set cut-off value such as 130/80. It is evident that anti-hypertensive therapy was not always started when a patient met criteria for hypertension, suggestive of therapeutic inertia in this population.th percentile for males and females at this height, thus we used that as our cut-off measurement for the analysis.Given the sporadic and sometimes incomplete nature of data received from some individuals, we are unable to report by percentile according to height, so instead tabulated data by the pressures themselves. The average adult height of males and females with MOPDII is approximately 100cm . AccordiSeventy two percent (n=34) had at least one documented blood pressure over 110/70mmHg , with 66% (n=31) having a documented blood pressure higher than 120/80mmHg , and 47% (n=22) having a documented blood pressure higher than 130/80 . A majority of individuals in each blood pressure range had an elevated measurement recorded on at least 3 separate occasions.As Fig.9/liter, which occurred in an individual with both MOPDII and Factor V Leiden.Table Fifty eight percent of individuals (15 of 26 with results) had hypercholesterolemia (defined as cholesterol>200mg/dl), at a mean age of 18years old; 13 of these individuals were treated with various statins. The two not noted to be under treatment were the youngest, with hypercholesterolemia detected at 5 and 6years of age.Insulin resistance was recorded for 39% (18 of 46 with results), including some with frank diabetes. Mean diagnostic age of insulin resistance was 12years, and mean age of type II diabetes diagnosis was 14years of age. Treatment included: metformin, insulin, pioglitazone, linagliptin, ezetimibe, and exenatide, with the majority treated by metformin and/or insulin..s exhaustive literature review in 2004 [Our primordial registry was conceived over a decade ago out of the hope from many families with MOPDII, that by gathering data together, we would be able to better understand why there did not seem to be any older adults with this diagnosis. Hall et al in 2004 , 24. TheThe questionnaire for our MOPDII vascular substudy was complicated, given the details needed to make this review as robust as possible, and the medical complexity of this condition for some individuals. We are surmising that it is for this reason that only 63% of families who consented for the substudy completed the survey in its entirety, as the duration of time needed for some families would be lengthy. A few of the families who did not complete the survey likely did not because they were clinic patients of ours, and we already are well-versed in their clinical course. However, there were also rather medically involved individuals for whom we were left with minimal information. Some individuals enrolled in the Primordial Registry were not included in this studys analysis, as no medical information was known besides their MOPDII diagnosis; we did not want to skew the results due to an inflated denominator. However, we posit that the data that remains is still the most comprehensive compendium of its kind for individuals with MOPDII.Through presymptomatic screening as well as with imaging performed after clinical signs present, our data demonstrate that about two thirds of individuals developed neurovascular disease, with half of all individuals developing intracranial aneurysms, approximately half identified with moyamoya, and a third with both diagnosed Table . Our resAs our current data show, MOPDII is also associated with vasculopathies beyond the neurovasculature. In our relatively large cohort of an exceedingly rare disease, renal artery stenosis, renal aneurysms, carotid and coronary artery disease were noted. These have not been benign processes; individuals with these findings have gone on to have kidney infarcts, kidney transplantation, and/or myocardial infarctions. Therefore, cardiac and renal screening appears warranted in this population. Although, the precise nature and frequency of screening is not yet fully developed.This association is not isolated to MOPDII. Diffuse vascular disease has been identified in other genetic conditions, such as those associated with ACTA2 , YY1AP1 31., 2011 [Diabetes and insulin resistance are additional important contributing factors, with over a third of individuals in our cohort with one of those diagnoses.  These ., 2011 , 34. Sin., 2011 , 34, scr., 2011 .Fourteen individuals in this cohort trialed human growth hormone replacement. Some stopped after a few months, and others continued for years. Of these, 71% (10) developed insulin resistance and/or frank diabetes later in life. While true that eight other individuals developed insulin resistance in the absence of growth hormone supplementation, given the published added risks and inefficacy of this treatment , would rFor the individuals with MOPDII in this study, chronic kidney disease (CKD) appeared independent from renal vascular disease, and is at a frequency that warrants screening as well. CKD itself is associated with a high risk of coronary artery disease, with an elevated risk of cardiovascular mortality beyond that associated with often concomitant hypertension and diabetes . Of our In our MOPDII cohort, approximately half of all the individuals have been diagnosed with hypertension or pre-hypertension. More specifically, one of these clinical diagnoses were recorded in 64% of individuals with a history of moyamoya, 76% with a history of intracranial aneurysms, 88% with a history of myocardial infarctions, and 100% with a history of chronic kidney disease (stage 3 or higher). These are not insignificant numbers, and as we posit above, the true proportions are possibly higher than this since providers are likely under-diagnosing hypertension in this population.There are recommendations to monitor blood pressure in MOPDII , 12, 15,From what we could deduce with the current data, 110/70mmHg should be a good starting point as an upper limit for blood pressure, monitored at each medical encounter, especially if the individual has a history of neurovascular disease, chronic kidney disease and/or diabetes. For individuals with height dramatically less than the mean for MOPDII, blood pressure should likely be lower yet. This is an area that needs further in-depth study. We provide this only as a starting point, as we implore medical providers to be aware of the complexities involved for this population. Untreated hypertension can have catastrophic effects at young ages for those with MOPDII, so should be monitored closely. Also, it is important to not overlook that acute hypertension should be investigated by imaging before treatment, because the etiology could be neurovascular disease or vascular disease elsewhere.As there are so many variables involved, it may be too difficult to completely tease things out at this juncture. Given the timeline of events and discovery of the natural history of disease, todays adults with MOPDII were getting their first presymptomatic screening for neurovascular concerns in adolescence; many finding treatable conditions at first image. A majority of the individuals who had myocardial infarctions as young adults had moyamoya diagnosed as teenagers or later, and did not have neurovascular imaging to screen starting in infancy as many children now do. This group of individuals likely had chronic hypertension for years without identification and treatment, which certainly could contribute to all the subsequent sequelae of medical complications that are now evident.Children with MOPDII entering adolescence right now may have a different natural history of disease, as one variable should be eliminated if they have had access to brain MRA or CTA modalities at birth and onward, given the recommendations for neurovasculature screening starting at diagnosis for moyamoya and aneurysms published a decade ago. However, even if neurovascular disease could be detected presymptomatically, and fully treated without sequelae, that is likely not the end of the story as there are multiple people with MOPDII who have had coronary artery disease or chronic kidney disease along with normal neurovascular screens.As the registry has been in existence for over 10years, many families had consented into the original project, but had stopped proactively sending medical records into the repository. Updated consents would be signed over the years, to allow us to reach out to their treating physicians for records as needed. There were some individuals that died between enrollment in the registry and this substudy. Given the nature of this project, those would be the most important records to identify and obtain. However, considering the sensitive nature of the circumstance, multiple of these families were either not responding to our inquiry, or once contacted, were not interested in participating in the survey or providing updated record releases. For these families we are only aware tangentially of what occurred for their child, which was not included in the larger analysis because the finer details could not be obtained.This data underscores the high burden of vascular concerns in this population. Though screening regimes have been published and put in place worldwide for neurovascular issues such as moyamoya and intracranial aneurysms, there are no evidence-based guidelines for screening for the other vascular manifestations. There has also not yet been a focused study on hypertension in this population, which would be an important avenue for further research.To this end, we recommend the following care guidelines for individuals with MOPDII:As previously published, to screen for neurovascular disease, recommend brain MRA/I at diagnosis and every 1218months thereafter in childhood , 14. ThiDue to structural abnormalities noted above, recommend renal ultrasound at diagnosis. Also, because chronic kidney disease appears independent from renal vascular disease, recommend assessments of renal function starting at age 5 . The mosGiven structural abnormalities noted, echocardiogram is recommended at diagnosis. Blood pressure should be monitored annually , with a Hypercholesterolemia is another comorbidity which should be screened for and treated appropriately once detected.Though not specifically studied here, lifestyle interventions associated with lower blood pressure could certainly be considered to minimize other contributing factors, to include: DASH diet, avoidance of high sodium foods, physical activity, and weight management .It cannot be underscored enough that any signs of myocardial infarction  should be taken seriously, given the relatively high incidence at a young age in this population.Additionally, when performing any needed catheterizations, extreme care should be taken, given the known postoperative complications with femoral artery stenosis.Given the additional negative impact of diabetes for individuals with already a high risk of cardiovascular disease, recommend screening to begin at age 5years, to ensure it is identified and treated at the earliest stage . LaboratA majority of the authors of this study have been involved with the national support group for primordial dwarfism for many years. We have been thrilled to see neurovascular screening protocols appear to save lives, to then witness with a heavy heart young adults succumbing to other unanticipated maladies. We are hopeful for the day that we can be a step ahead of all the life-limiting conditions associated with MOPDII. Knowing the landscape is one thing, and knowing how to navigate it is another. We are optimistic this survey is the first step in helping to unravel the key to best take care of individuals with MOPDII.


In children with autosomal dominant polycystic kidney disease (ADPKD), clinical manifestations range from severe neonatal presentation to renal cysts found by chance. We aimed to evaluate demographic, clinical, laboratory findings, and genetic analysis of children with ADPKD. We evaluated children diagnosed with ADPKD between January 2006 and January 2019. The diagnosis was established by family history, ultrasound findings, and/or genetic analysis. The demographic, clinical, and laboratory findings were evaluated retrospectively. Patients <10 years and ≥10 years at the time of diagnosis were divided into 2 groups and parameters were compared between the groups. PKD1mutations in 21,PKD2mutations in 1, no mutation in 3). Cysts were bilateral in 35 (85%) of the patients. Only one patient had hepatic cysts. No valvular defect was defined in 12 patients detected. Only 1 patient had hypertension. None of them had chronic kidney disease. No difference could be demonstrated in sex, laterality of the cysts, maximum cyst diameter, cyst or kidney enlargement, follow-up duration, or GFR at last visit between Groups 1 and 2.  There were 41 children (M/F: 18/23) diagnosed with ADPKD. The mean age at diagnosis was 7.2 ± 5.1 (0.6–16.9) years and the follow-up duration was 59.34 ± 40.56 (8–198) months. Five patients (12%) were diagnosed as very early onset ADPKD. All patients had a positive family history. Genetic analysis was performed in 29 patients (The majority of children with ADPKD had preserved renal functions and slight cyst enlargement during their follow-up. However, they may have different renal problems deserving closed follow-up.  PKD1, located on chromosome 16p13.3, andPKD2, located on 4q21, encoding polycystin-1 and -2, respectively . Autosomal dominant polycystic kidney disease  is the most common hereditary renal disorder [1]. It is characterized by cystic dilations generating from any part of the nephron with enlarged kidneys and occurs in 1:1000 live births . The disease is genetically heterogeneous and the genes involved areMost patients with ADPKD present as adults; however, the timing of cyst generation may be discrete leading to the antenatal period. Cysts enlarge by age. Cyst burden may be significant in childhood and renal failure typically develops in the sixth decade [1]. Why some cases of ADPKD present in childhood is unclear, because there is no evidence for genetic heterogeneity [2]. Screening and monitoring is controversial in the childhood [2].Polyuria/polydipsia is usually the first biological renal manifestation, which is associated with decreased concentrating ability . Other renal manifestations include flank pain, hematuria, proteinuria, hypertension, nephrolithiasis, urinary tract infections, infection of the cysts, or hemorrhagia into the cysts [1–3]. It is a systemic disorder and extrarenal manifestations including hepatic, pancreatic or seminal vesicle cysts, cerebral aneurysms, aortic aneurysms and dissection, coronary artery aneurysms, colonic diverticula, abdominal wall and inguinal hernia and cardiac valve disease may occur . Although they are well-defined in adults, diagnostic criteria and management consensus are uncertain in children. In this study, we evaluated demographic, clinical, laboratory findings, and genetic analyses of our patients with ADPKD. We aimed to report familial burden, genetic contribution, cyst characteristics, renal and extrarenal manifestations, treatment options and follow-up modalities in a series of children being followed up in our clinic for a relatively long period and demonstrated whether these parameters differed between cases diagnosed in the first decade or thereafter. PKD1,PKD2,andPKHD1mutations.We evaluated children diagnosed with ADPKD between January 2006 and January 2019. The diagnosis was established by family history, ultrasound findings, and/or genetic analysis. The demographic, clinical, and laboratory findings including age at diagnosis, sex, follow-up duration, parental inheritance pattern, the number of people diagnosed with ADPKD in the family, renal manifestations including laterality of cysts, number and diameter of the largest cysts at first and last visit in each kidney on ultrasound, extrarenal manifestations, evidence for hypertension (HT), kidney stone, urinary tract infections (UTIs), hematuria, proteinuria or pyuria, GFR at the last visit and genetic mutations (if available) were evaluated retrospectively. Children diagnosed in utero or within the first 18 months of life were grouped as very early onset (VEO) ADPKD [2]. Genetic analysis has been performed by Sanger sequencing until a few years ago. Only PKD1 mutation could have been defined by this method. Then, next-generation sequencing went into use for screening bothCyst enlargement per month (CEM) was estimated by the formula: Δ cyst diameter (diameter of the largest cyst at last visit – diameter of the largest cyst at first visit/follow-up duration). Kidney enlargement per month (KEM) has been determined for both right and left kidneys by the following equation: Δ kidney length (kidney length at last visit – kidney length at first visit)/follow-up duration. The highest KEM was recorded. Hypertension was defined as blood pressure ≥95 percentile for height and sex. Pyuria was defined as ≥5 white blood cells/mm3 and microscopic hematuria was defined as ≥5 red blood cells/mm3. Proteinuria was defined as a protein/creatinine ratio >0.21 in the spot urine sample or ≥4/mg/m2/h in 24-h collected urine. The estimated glomerular filtration rate (eGFR) was calculated due to the Schwartz formula as follows: eGFR = k x height in cm/serum creatinine. Since the serum creatinine is determined by Jaffe’s reaction in our laboratory, we used 0.55 for girls and boys younger than 13 years and 0.7 for boys ≥13 years for constant k, which is directly proportional to the muscle component. Glomerular hyperfiltration (GHF) was defined as GFR ≥140 mL/min/1.73 m2 [4].Patients were divided into 2 groups due to their age at diagnosis arbitrarily. Patients <10 years at the time of diagnosis were grouped as Group 1 to present patients diagnosed in the first decade. Patients, those ≥10 years were diagnosed as Group 2. The parameters described above were compared between the groups. Statistical analyses were performed using IBM SPSS 22.0 . Kolmogorov–Smirnov test was used to evaluate the normal distribution of continuous variables between the groups. The continuous variables were presented as either mean ± standard deviation or median (25p–75p) according to data distribution and categorical variables were presented as percentage. The parameters with normal distribution were compared by Student’s t-test, whereas those without normal distribution were evaluated by Mann–Whitney U test. The categorical variables between the groups were compared using the chi-square test. Depending on the distribution type of the variables, Pearson or Spearman correlation analysis was performed. A P value of <0.05 was considered significant in all statistical evaluations.There were 41 children diagnosed with ADPKD in the mentioned period. Of those patients, 18 (44%) were male and 23 (56%) were female. The mean age at diagnosis was 7.2 ± 5.1 (0–16.9) years. Five patients (12%) were diagnosed as VEO ADPKD. The mean follow-up duration was 59.34 ± 40.56 (8–198) months. A family history of ADPKD was known at admission in all patients. Inheritance was maternal in 20 (49%) and paternal in 21 (51%) of them. Twenty (49%) of the patients were siblings belonging to 9 families. The mean number of patients diagnosed with ADPKD in the family were 4.33 ± 1.81 (1–7). PKD1mutation was found by Sanger sequencing. In the rest of the group detected by next-generation sequencing, no mutation could be detected in 3 patients, while 1 hadPKD2mutation and 21 hadPKD1mutation. Of the 5 VEO patients, 2 had in utero cysts and early diagnosis as their parents had the disease and requested screening for ADPKD. Of the latter two, one had a stop codon mutation, while the other had a missense mutation (Table 2).Genetic analysis could have been performed in 29 (70%) of the patients (Table 1). In 4 of them,Renal cysts were bilateral in 35 (85%) of the patients. The remaining three had cysts on the left and three had cysts on the right kidney at the first visit and three of them had bilateral cysts at last visit. The mean diameter of the largest cyst at the last follow-up was 14.49 ± 9.5 (2–60) mm. The calculated CEM was 0.19 ± 0.2 (–0.13–0.77) and KEM was 0.31 ± 0.13 (–0.15–0.54). Only one patient had hepatic cysts, and none of them had splenic or pancreatic cysts. Cranial magnetic resonance angiography was performed in 5 patients and none had an aneurysm. Echocardiography was performed in 12 of the patients that were normal in 11 and demonstrated PFO in one of them.Recurrent UTIs were detected in 6 (14%), HT was observed in 1 (2%), urolithiasis was defined in 3 (7%), proteinuria in 6 (15%), pyuria in 4 (10%), and hematuria in 5 (12%) of the patients. None had chronic kidney disease in the follow-up and mean GFR at the time of the last visit was 127.3 ± 21.8 (89.8–172) mL/min/1.73m2. No difference could be demonstrated in sex, laterality of the cysts, maximum cyst diameter, CEM, KEM, follow-up duration, or GFR at last visit between Groups 1 and 2 (Table 3). Besides, there was no significant correlation between the GFR values at the last visit and the maximum cyst diameter , CEM , KEM  or follow-up duration . Autosomal dominant polycystic kidney disease is the most common monogenic renal disorder causing renal failure all over the world . Although end-stage kidney disease is expected in the sixth decade and it is controversial to diagnose at-risk children, patients diagnosed with ADPKD in childhood are becoming more common. In this study, we reviewed our 41 patients with ADPKD diagnosed in childhood. Five of them were diagnosed in the first 18 months of their lives, so called “VEO” ADPKD with two being diagnosed in utero.  In ADPKD, clinical manifestations range from severe neonatal presentation to renal cysts found by chance in the childhood period [2]. Why some ADPKD cases present in childhood is unknown and the type of mutation was thought to be the underlying factor. It is well-known that patients with a truncating mutation are more severely affected [2]. Children diagnosed as VEO ADPKD also represent a high-risk group. They are known to have more HT and progression to chronic kidney disease (CKD) at a median age of 16 years [2]. Five of our patients (12%) were diagnosed with VEO ADPKD. Mothers of all five children were also diagnosed with ADPKD and one also had a sister with the disease. Two of them had an antenatal diagnosis due to cysts determined in utero. Of the latter two cases, five and four other relatives except their mothers were diagnosed with ADPKD, respectively. Both had bilateral multiple cysts with the largest diameter of >10 mm in the antenatal and early postnatal periods. The first case had a nonsense mutation resulting in a stop codon, while the other case had a missense mutation. PKD1 orPKD2,encoding polycystin-1 (PC1) and -2 (PC2), and accounting for 85 and 15% of the patients, respectively . Recently, a third gene, namelyGANAB ,has been identified to cause ADPKD [2]. Most cases are familial, however, family history is lacking in 10%–25% of patients including de novo disease in up to 10%–15% [6]. In our series, all the cases had a maternal or paternal history of ADPKD and none had a de novo condition at all. Twenty-five patients hadPKD1and only 1 patient hadPKD2mutation. Unfortunately,PKD1mutations are known to be associated with a more severe disease course and progress to end-stage renal disease 20 years earlier than those withPKD2mutations and those with the latter mutation have fewer renal cysts [1]. It is hard to comment on this topic with only one patient with PKD2 mutation, however, our patient had a relatively low number of cysts. In two of our patients, no identifiable mutation was found, although they all had bilateral cysts and positive family history, and one additionally had VEO ADPKD. We may speculate that they had mutations that had not been identified yet or they may have mutations inGANAB, which cannot be checked in the genetic laboratory that we used to work with.The genes responsible for ADPKD areA consensus for the diagnosis, screening, treatment, or clinical care of children with ADPKD has been lacking until recently [2]. Diagnosing ADPKD is still challenging in children <15 years due to the lack of definitive criteria. Although not validated, a child with positive family history and a single cyst preferably >1 cm is generally assumed to have ADPKD [2]. Genetic analysis may also complete the diagnosis in a suspicious case, however may result in negative, as seen in our two cases. Recently, a new clinical practice guideline has been published on monitoring children with ADPKD [7]. Screening is generally not recommended in presymptomatic children due to insurability and emotional problems . Diagnosing a child may cause difficulties in obtaining insurance in some countries. In addition, it has been demonstrated that 22% of the parents have fallen into depression and 62% feel guilty about their children’s disease [9]. In Kidney Disease Improving Global Outcomes (KDIGO) consensus guideline, screening presymptomatic children at risk with ultrasound or genetic testing is not recommended [10]. However, 3 different options for parents have been offered: not to screen; to screen as young as possible and disclose the results only to the parents, or to screen and disclose the results to the whole family [10]. In the European ADPKD Forum, genetic analysis has been defined as vital for diagnosis in children, but screening for at-risk children has not been discussed [2]. In the recent clinical guideline, discussing the potential harms and benefits of being diagnosed with the family and the child if possible, has been recommended [7]. In our series, patients were mostly brought to our clinic by their parents to learn whether the child has the disease, while in 19% of them, cysts were defined in their ultrasound coincidentally. However, family history was defined in almost all children when asked or cysts were demonstrated in the ultrasound (US) of their parents. No definite treatment has been established for children with ADPKD yet. That is another reason for ADPKD to be controversial to screen. Tolvaptan, statins, angiotension converting enzyme inhibitors (ACEIs), and mTOR inhibitors may be used in adults. Currently, V2-receptor antagonist tolvaptan is the only drug available for selected adults  to slow the progression of cyst development and renal insufficiency [11]. There is no enough evidence to use tolvaptan in children routinely, however, it has been used in a case with severe neonatal ADPKD [12]. The results of an ongoing phase IIIb double-blind, placebo-controlled study for tolvaptan treatment in children with ADPKD aged 4–17 years is pending [13]. Another treatment of choice in pediatric ADPKD is statins. In a 3-year randomized, double-blind, placebo-controlled study in children with ADPKD aged 8–22 years demonstrated that pravastatin may slow down the progression of kidney disease [14]. However, statin use in that age group is not safely advisable. A 5-year study on the effects of ACEIs in patients with ADPKD aged 4–21 years could not demonstrate any benefit on renal growth [15]. Due to the side effects and disappointing results in adults, mTOR inhibitors have no place for treatment in children with ADPKD as well [16]. Thus, none of our patients were on routine treatment. It is well-known that disease progression can be prevented by modifiable factors including proteinuria and hypertension . In a metaanalysis, Marlais et al. have found that 20% of children with ADPKD have HT [17). They have observed that many children with ADPKD are not under regular follow-up and have recommended regular blood pressure control for all children at risk for ADPKD [17]. In KDIGO, it is recommended to screen children with a family history of ADPKD for HT from the age of 5 years and to repeat blood pressure measurements at 3 year intervals in case the patient is normotensive [10]. In the recent clinical guideline, blood pressure monitoring at least once every 2 years has been recommended for children aged 5 years and above and diagnosed with ADPKD or those at risk for developing the disease [7]. Target blood pressure limits have not been established well for children with ADPKD. In KDIGO, a goal blood pressure <90th percentile for age, sex, and height with renin-angiotensin-aldosteron system blockade as first-line treatment has been offered [10]. However, in a more recent study, a goal blood pressure ≤50th percentile with ACEIs has been reported to correlate with better eGFR and left ventricular mass index levels [14]. In addition to HT and proteinuria, glomerular hyperfiltration (GFH) is also a bad prognostic factor associated with a significantly faster renal function impairment and a higher renal growth rate [18]. Only 1 of our patients had HT and was put on ACEI, and 6 had orthostatic proteinuria. 26% of our patients had GHF and fortunately, none had a GFR lower than 90 mg/mL/1.73m2 during the follow-up period. Other nephro-urological problems in ADPKD include hematuria, pyuria, urinary tract infections, or nephrolithiasis [1]. Hematuria was detected in 12%, pyuria was detected in 10%, UTIs were detected in 14%, and urolithiasis was defined in 7% of the patients in our series. It is well-known that ADPKD is a systemic disorder causing cyst formation in other organs, mostly in the liver and pancreas, intracranial arterial aneurysms, cardiac valvular defects, inguinal and abdominal herniation, in addition to nephro-urological problems. Only one of our patients had hepatic cysts, and none had a splenic or pancreatic cyst. Screening children for intracranial aneurysms is uncertain. However, there is recent evidence that screening all patients regardless of the family history of aneurysms is cost-effective [19]. We have not routinely searched for intracranial aneurysms, however, 5 of our patients had MRA without any evidence of intracranial aneurysms. Echocardiography was performed in 12 of the patients that were normal in all but one with PFO. Height-adjusted total kidney volume (TKV) has been proven to be a strong and independent predictor for end-stage renal disease (ESRD) development in ADPDK [2]. We could not measure TKV in our patients. Instead, we have assessed the kidney sizes and cyst diameters obtained by ultrasonography and changes in them throughout the follow-up period. In adults, the total kidney and cyst volume enlargement rate slow down with age. In children, they are higher than adults and highest during puberty [1]. However, we could not exactly define such a correlation between the follow-up duration and cyst enlargement. In addition, age at diagnosis has no influence on cyst or kidney enlargement during the follow-up. The results of our study should be interpreted with its limitations. The first was the retrospective design of our study and the second was the limited number of cases. As recommendations for screening was unclear, not all our patients had evaluation for intracranial aneurysms, which is another limitation. Finally, not all the cases had genetic analysis and this prevented a definitive analyses about the correlations of mutations and the clinical entities. The majority of children with ADPKD in this study were found to have preserved renal functions and slight cyst enlargement during their follow-up supporting the debate about diagnosing children at-risk. However, early precautions have the potential to delay progression to ESRD and the patients may have different renal problems deserving closed follow-up. It would be more valuable to diagnose those children at-risk if ongoing trials define effective treatment strategies for cyst enlargement. The authors declare that no funding was received for the present study. The study was approved by the ethics committee of our institute . All procedures involving “Human beings” were conducted following the ethical standards and principles outlined in the Helsinki Declaration 2008. Informed consent for participating in this study was not required.