There is uncertainty about the long-term risks of living kidney donation. Well-designed studies with controls well-matched on risk factors for kidney disease are needed to understand the attributable risks of kidney donation.The goal of the Minnesota Attributable Risk of Kidney Donation (MARKD) study is to compare the long-term (> 50 years) outcomes of living donors (LDs) to contemporary and geographically similar controls that are well-matched on health status. University of Minnesota  and Mayo Clinic LDs  will be matched to Rochester Epidemiology Project (REP) controls (approximately 4 controls to 1 donor) on the basis of age, sex, and race/ethnicity. The REP controls are a well-defined population, with detailed medical record data linked between all providers in Olmsted and surrounding counties, that come from the same geographic region and era (early 1960s to present) as the donors. Controls will be carefully selected to have health status acceptable for donation on the index date (date their matched donor donated). Further refinement of the control group will include confirmed kidney health  and matching (on index date) of body mass index, smoking history, family history of chronic kidney disease, and blood pressure. Outcomes will be ascertained from national registries  and a new survey administered to both donors and controls; the data will be supplemented by prior surveys and medical record review of donors and REP controls. The outcomes to be compared are all-cause mortality, end-stage kidney disease, cardiovascular disease and mortality, estimated glomerular filtration rate (eGFR) trajectory and chronic kidney disease, pregnancy risks, and development of diseases that frequently lead to chronic kidney disease . We will additionally evaluate whether the risk of donation differs based on baseline characteristics.Our study will provide a comprehensive assessment of long-term living donor risk to inform candidate living donors, and to inform the follow-up and care of current living donors.The online version contains supplementary material available at 10.1186/s12882-023-03149-7. For others, a decrease of GFR with aging or new onset disease will subsequently result in GFR less than 60 ml/min/1.73m2. Numerous studies in the general population have shown that individuals with GFR of less than 60 ml/min/1.73m2 have increased long-term risks including continuing loss of kidney function and higher rates of cardiovascular disease (CVD) and mortality [A living donor kidney transplant is the best treatment option for a patient with end-stage kidney disease (ESKD) as it provides better patient and graft survival and quality of life than either dialysis or a deceased donor transplant –13. Howe donation, 60. Theer donors, 62. Sinortality –87. Thosortality –93.Several studies have sought to estimate the attributable risk of donor nephrectomy on mortality, ESKD, CVD, and other outcomes. Single-center and registry studies comparing LDs to the general population have not shown increased long-term CVD, ESKD, or mortality risk , 44–54. In a review of studies reporting increased long-term risk for LDs, Janki et al. identified that both the Norwegian study reporting an increased risk of CVD, mortality, and ESKD, and the US study reporting increased risk of ESKD, selected non-donor control populations that were healthier than the donors, resulting in an over estimation of risk . In addiA key limitation in existing studies is that there was no determination of family history of chronic kidney disease (CKD) or ESKD for controls. In the Norwegian study, all 9 donors who developed ESKD were first-degree relatives of the recipient; in the US study, 83 of the 99 who developed ESKD were related to the recipient. Numerous studies in the general population have shown that individuals related to a person with ESKD have an increased risk of ESKD –122. WaiThere have only been a few studies of pregnancy risk postdonation , 125. StFinally, to date, most studies of LDs matched to healthy controls had limited follow-up. In the US study by Muzaale et al., the meanThe recognition of significant gaps in our understanding of long-term LD outcomes has resulted in calls for more complete long-term LD follow-up studies . In the To address these calls to action and limitations of existing studies, the Minnesota Attributable Risk of Kidney Donation (MARKD) study will compare the long-term risks for LDs from UMN and Mayo Clinic (first donation in 1963 and up to 60 years of follow-up) to the long-term risks for contemporaneous, geographically similar, healthy matched controls from the Rochester Epidemiology Project (REP). By reviewing medical records, we additionally plan to identify a subset of controls from the REP with known normal kidney function at a date corresponding to the date of donation and known family history of CKD and be able to match controls to LDs on these important risk factors. Consequently, we will provide the best data to date to inform prospective candidates of the long-term risks of kidney donation.This is a matched cohort study of LDs from UMN and Mayo Clinic with contemporaneous, chart-validated, healthy matched REP controls with an index date (date of donation for LD) between 1963 and 2012. This time frame was chosen since the focus of the study is on long-term (> 10-year postdonation) outcomes ; (c) whether the trajectory of eGFR differs between LDs and controls; d) whether there are differences in the above outcomes for those developing de novo kidney disease and/or disease that might affect the kidneys ; and e) whether there are differences in pregnancy outcomes  between LDs and controls. The overall hypothesis is that LDs will have relatively small, slightly increased, but clinically insignificant, differences in the incidence of ESKD, mortality, intermediate endpoints, and pregnancy complications compared to well-matched control groups.The MARKD study aims to determine long-term attributable LD risk by comparing well-matched controls with LDs. LDs will be compared with matched controls to determine: (a) whether LDs are at greater risk for the rare outcomes of mortality and ESKD; (b) whether LDs are at increased risk for CVD, cardiovascular mortality, and/or increased risk of intermediate measures of kidney disease  increase the sample size to increase the statistical power for analyses of certain outcomes  and (b) add a second site to assess the generalizability of findings. A summary of the clinical and demographic characteristics of the Mayo LD cohort is given in Table The development and use of the REP have been described in detail –145. In The REP represents the same geographical region as both the UMN and Mayo LDs with the same time frame starting in the 1960s, making it an ideal control group (reference cohort) for long-term follow-up.Our goal is to identify, for each LD, individuals in the REP database who would have been eligible for kidney donation on the same date as the LD based on the information in the medical record.Pilot studies:As we were unsure of the most efficient way to use diagnostic codes and chart abstraction for excluding controls that would not qualify as donors, we performed two pilot studies to optimize our selection of exclusionary codes and exclusionary criteria on chart abstraction.Supplemental Materials for a full list of exclusionary conditions.First, we identified all approximately 180,000 individuals who have not opted out of the use of their medical records for research (per Minnesota statute) in the REP Olmsted County cohort with a potential index date within the age and time period window of the donors. Within the REP, code sets have been developed for 355 different specific diseases using International Classification of Disease 9th and 10th revisions , Hospital Adaptation of the International Classification of Diseases (HICDA), and Berkson codes . On review of these code sets, we determined that 173 of these were conditions/diseases that if truly present, would always lead to exclusion as a donor. Of these exclusionary diseases, 26 were prevalent on or prior to the index date of at least 1,000 individuals within the REP. However, we did not want to exclude too many of our potential controls that were false positives for these exclusionary diseases. Thus, we (Drs. Matas and Issa) performed a manual chart review on 10 random individuals for each of these disease code sets. We found that some codes within these code sets corresponded to conditions that were true contraindications for donation , but some were for mild disease or other conditions which were not absolute contraindications . The individual codes for these 26 code sets were refined to better correspond to conditions that would be absolute contraindications for donation. Subsequently, all 173 exclusionary diseases (including the 26 that were adjusted to be made more specific for exclusion and less sensitive) were used to exclude individuals from being matched as controls. See Second, after excluding individuals with these 173 diseases, we performed a pilot study of 117 randomly sampled individuals to abstract in detail their medical status, available data at or prior to the potential index date and during follow-up, and any potential concerns with their candidacy as a kidney donor on the index date. From this pilot study, we identified 5 exclusionary conditions  that were relatively common and missed by the exclusionary code set. Psychiatric conditions, substance abuse, and hypertension are common and require medical record review as many are mild and do not warrant exclusion. Abnormal serum creatinine, urine protein, or body mass index (BMI) are simply underdiagnosed and, thus, require medical record review to be detected for exclusion.After finalizing the list of exclusionary codes, up to 4 potential controls were identified for every donor. All controls were residents of Olmsted County (or surrounding counties) at some point and lacked any exclusionary diagnoses before the index date (date of donation for the matched LD) or up to 1 year after the index date. The 1-year window after the index date was used because some diseases may be present on the index date but not diagnosed due to the intermittent nature of clinic visits in the medical record. This matching was accomplished first for the UMN donors and then for the Mayo Clinic donors. These potential REP controls were initially identified based on the following requirements: (1) Olmsted County or surrounding county resident at index date, 2) at least one REP encounter prior to index and at least one REP encounter one year or more after index, (3) age difference between LD and potential REP control at index less than 5 years, and (4) exact match on broad racial categories (Black vs. non-Black). If more than four controls meet these criteria, the four best controls based on (1) exact match on more granular racial categories , (2) exact match on ethnicity , and (3) minimum difference in age at index was selected. If fewer than four controls were identified, the matching criteria were broadened to allow for unknown county of residence at the index date and subsequently known non-resident of Olmsted or surrounding counties at the index date. The full algorithm is provided in Fig.  at least2), history of recent cancer (other than non-melanoma skin cancers), severe depression/anxiety (untreated and interferes with lifestyle), history of urological abnormalities , heart disease, liver disease, and chronic obstructive pulmonary disease.Subsequently, all identified potential control charts (paper and electronic) are being manually reviewed and abstracted into a REDCap database by the abstraction team, which consists of a nurse practitioner who previously worked in a kidney transplant clinic, nurses, and medical research trainees. Abstraction guidelines with screenshots of the database are maintained and updated as needed for use by all abstractors. After orientation is completed, each abstractor completes a set of 20 cases to ensure consistency with these guidelines. Chart abstraction involves two steps: (1) validation of the potential control , and then, if valid: (2) capturing clinical and laboratory data. The validation step involves reviewing medical records prior to the index date for contraindications for kidney donation. The following conditions are often found by abstractors resulting in exclusion of possible control: hypertension (blood pressure over 140/90 mm Hg), Proteinuria , impaired kidney function , non-tobacco substance abuse , obesity , may be rematched to a different donor at a different index date.Similar to the donor candidate assessment, certain conditions are allowed for controls at the time of index if they are otherwise healthy. A BMI of 35–40 kg/mIf it is unclear if a certain control would have been eligible to donate given their medical history, a review by kidney donation experts  is used to approve or exclude the potential control. The abstraction guidelines are subsequently updated to ensure future consistency. In addition, the abstractor team meets monthly after completing a reliability chart (same chart for each abstractor) to ensure similar abstractions among the abstractor team.If a control is validated, abstractors proceed to collect additional baseline and follow-up data. This includes any mention of family history of DM, hypertension, CKD, or ESKD. We obtain the closest laboratory data measures before and after the index date for baseline. These measures include: height, weight, blood pressure (avoiding blood pressure obtained during visits to the emergency department), serum creatinine, blood urea nitrogen (BUN), serum glucose, urine glucose, and any assessment of proteinuria/albuminuria (avoiding those with concurrent urinary tract infections).Outcomes include mortality, CVD and cardiovascular mortality, serial creatinine (to determine eGFR trajectory and chronic kidney disease) and other laboratory measures, pregnancy outcomes and complications, and development of diseases that frequently lead to CKD . Outcomes will be ascertained from national registries, medical record review of donors and REP controls, and a new survey administered to both donors and controls. A list of data collected, data source, and frequency of data collection is provided in Table To determine mortality/causes of death and ESKD, patient identifiers  for the UMN and Mayo donors and the REP controls will be sent in a secure manner to the NDI and to the USRDS, respectively.Once a control is validated, as noted above, abstractors collect follow-up data from the medical record. Lab measures obtained after index are limited to up to one value per calendar year and include: weight, blood pressure, serum creatinine, serum glucose, BUN, serum creatinine, and urine protein. For efficiency of abstraction, the database is prefilled with all electronically available values from the medical record and then validated by the abstractor. Finally, clinical diagnoses and the year they occurred are recorded from the medical record.As described above, when UMN LDs are surveyed, they are also asked to provide recent lab test results and copies of medical records. At the time of survey administration, abstractors collect follow-up data from medical record of the UMN health system and affiliated clinics. With LDs’ permission, UMN investigators will contact other clinics for recent medical records that include clinical notes and laboratory test results.Supplemental Materials for the survey). We will additionally capture cancer information to use as a negative control .UMN donors and validated REP controls not known to be deceased will be sent a standardized survey to determine outcomes. This survey is based on the existing survey that has been used for UMN donors, but modified to be usable with both LDs and controls. This survey supplements the capture of key data that may not be consistently documented in the medical record with specific items including: hematuria or proteinuria of at least 6 months duration, hypertension, DM, heart failure, myocardial infarction, angioplasty or stent, angina, smoking history, and pregnancy history; and family history of hypertension, DM, or ESKD . After surveying the first validated control for each REP donors, we will prioritize surveying controls for donors who lack completed surveys by a matched control.We have established a secure database to combine data from each source. The same combination of manual review, quality control reports, and built-in logic checks that has been used to ensure data quality for UMN LD survey responses will be used for all surveys in this study to ensure the integrity of the data. This study has been approved by the Institutional Review Boards of the University of Minnesota and the Mayo Clinic.Although the REP control matching algorithm outlined in Sect. primary analysis, we consider controls for whom we can ascertain BMI, systolic and diastolic blood pressure, use of anti-hypertensive medications, smoking history, and known normal serum creatinine, normal blood urea nitrogen (particularly relevant in the 1960s where serum creatinine testing may not have been done), or normal urine protein  identified within 10 years prior to the index date (minimize detection bias as we avoid any controls who may have had unrecognized kidney disease due to absence of kidney function testing). We additionally will attempt to include family history of CKD at the index date (either through chart review or from survey results) as a factor in the matching. Urine protein tests allowed are comprehensive . However, we expect most will be urine dipstick proteins. Normal is defined using the reference range at the time of the test. Our preliminary data suggested that younger controls will often not have a baseline serum creatinine level, though about half will have a urine protein assessment. Since most kidney disease in younger adults is proteinuric, a normal urine protein test in younger adults (age < 50 years) will be considered sufficient for inclusion in this analysis.For the We plan to use optimal, sparse 1:k matching with refined covariate balance, 149 to In addition to the set of controls selected for the primary analysis, we will consider additional broader groups from the REP from which to match. As in the primary control group, we plan to use sparse optimal 1:k matching to match REP patients in these groups to LDs.i)REP patients for whom we can ascertain BMI, systolic and diastolic blood pressure, diagnosis of hypertension, smoking history, and normal renal function . This group does not consider family history of CKD.ii)REP patients for whom we can ascertain BMI, systolic and diastolic blood pressure, diagnosis of hypertension, and smoking history with no known abnormal renal function . This group does not consider family history of CKD or require renal function testing to have been done.iii)A group that does not consider family history of CKD, require renal function testing to have been done, or consider clinical characteristics .iv)Additionally, we will construct control groups using matching algorithms as close as possible to those used in previous studies, 56 to aFor each control group (primary and sensitivity cohorts) we match to LDs, we will estimate the incidence rate of each outcome.2), proteinuria, DM, and hypertension after index date between LDs and healthy controls. Our study is powered based on these analyses. Cox proportional hazards models will also be used to test for an increased risk of adverse outcomes in living LDs versus controls while directly accounting for the variables used for matching . In analyses involving Mayo LDs and their associated controls we will account for donation center (Mayo vs. UMN) as a covariate in the model. If the proportional hazards assumption fails, an alternative method such as an accelerated failure time model will be considered. Indeed, the risk of mortality and ESKD may disproportionately increase with long-term follow-up on the 60-year scale of this study [Log-rank tests and Kaplan Meier curves will be used as preliminary assessments to compare the risk of all-cause mortality and cardiovascular mortality, CVD, ESKD, CKD  by testing the significance of the interaction term between donation and the characteristic in the model. These models will also allow us to assess the attributable risk of donation in LDs with certain characteristics at donation. We will specifically assess if age, BMI, smoking, donation eGFR, and race/ethnicity modify the effect of donation on ESKD and mortality. As a sensitivity analysis, the analyses will be repeated using a subset of REP controls having at least 5 years of medical history preceding the index date.Logistic regression models fit using generalized estimating equations will be used to test for differences in the odds of gestational hypertension and preeclampsia between LDs and controls for all pregnancies occurring after the index date, while accounting for women having potentially multiple pregnancies. Adjustment variables to be considered in the model include: race/ethnicity, age at pregnancy, gravidity, and previous occurrence of pregnancy complications. Secondary analyses using logistic regression models will test for differences in the odds of these complications in the first pregnancy after the index date, adjusting for having previous pregnancies, and second pregnancy after the index date, adjusting for the occurrence of pregnancy complications in the first post-index date pregnancy.A linear mixed effects model will be used to test the difference in the trajectory of eGFR over time between living LDs and healthy controls. This model will initially have a linear effect for time with subject-specific random intercepts and slopes, but natural splines will be used to investigate nonlinear temporal trajectories.Given the results identified using preliminary matching algorithms and chart review we assume that we will be able to identify 3 controls for 98% of LDs and at least one of those controls will be included in a more restrictive matched subset . For the following power analyses, the type-1 error probability is set to 5%.For estimating the minimal detectible hazard ratio for all-cause mortality, we note that at present, 12% of UMN LDs, 7% of all Mayo LDs, and 11% of identified preliminary controls are deceased. With a mortality rate of 11% in our study population, we estimate that our minimal detectible hazard ratio with 80% power will be 1.13 for a 3:1 matching and 1.16 for a 1:1 matching.2 during follow-up. In our analysis comparing the risk of developing an eGFR < 45 between UMN LDs and healthy controls, we conservatively estimate that eGFR < 45 will develop in approximately 8 to 14% of our study population. With this assumption, our minimal detectable hazard ratio will be between 1.20 and 1.15 for a 3:1 matching and between 1.25 and 1.18 for a 1:1 matching.In UMN LDs, approximately 13.5% have developed eGFR < 45 ml/min/1.73mAmong the 301 UMN LDs who developed DM after donation without first developing CVD, 57 individuals (19%) later developed CVD. Assuming identification of a 1:1 match for approximately 80% (240) of these donors and that the overall proportion of individuals in our study population who develop CVD after DM ranges from 15 to 23%, we will have 80% power to detect a hazard ratio between 1.94 and 1.70.The MARKD study will evaluate the attributable long-term risk of kidney donation by matching LDs from two transplant centers with controls from a large, contemporaneous, geographically similar epidemiological cohort. A similar study with the number of LDs and healthy matched controls and length of detailed follow-up could not be done anywhere else worldwide. While our geographic location is constrained in terms of ethnic/racial diversity, no other transplant centers have detailed long-term donor follow-up with a truly well-matched control group. The Norwegian study described previously has the longest healthy matched-control study to date . HoweverThe MARKD study will focus on LDs in two LD programs that started in 1963, and REP-controls dating back to 1963 with comprehensive medical records that are ongoing. A unique aspect of our study is the granular long-term follow-up. The UMN LD program has surveyed LDs every 3 years. The REP links the full life course medical records of nearly all Olmsted County providers, allowing electronic (ICD-9/10 codes) and manual (chart abstraction) review of the comprehensive medical record of controls. No other study of this size provides: (a) this length of follow-up (more than three decades longer follow-up than the US OPTN registry), and (b) detailed ongoing follow-up of LDs and healthy-matched cohorts. Developing a matched control cohort from the REP will not only allow us to provide the best and the longest data on long-term LD outcomes to date, but will also lay the groundwork for future analyses.A major innovative aspect of our study is our contemporaneous healthy matched control cohort. Unlike prior studies, we will more clearly delineate matched controls that reflect the health status of donors just prior to the date of donation. This will be accomplished by identifying controls known to be healthy and with normal renal function at the index date (matched to donation date) who are from the same geographical region of residence (Upper Midwest) as donors, and by obtaining granular data on controls to allow for optimal matching of controls to LDs on key characteristics (including family history of CKD).2, proteinuria). This will provide information about whether the impact of these comorbidities differs for those with 1 vs. 2 kidneys. That is, we will be able to assess if differences in long-term outcomes between donors and controls are mediated by differences in postdonation comorbidities.Longitudinal follow-up of both LDs and REP controls provides detailed, uniquely available health information on events preceding ESKD and mortality. In contrast to previous studies, we will compare LDs and healthy-matched REP controls on the much more common intermediate endpoints  that occur before ESKD or death. Additionally, we will be able to study outcomes of LDs who develop new comorbidities late after donation .Another strength of our study is uniform event ascertainment. Use of national databases , access to long-term historical data, and a new survey sent at the same time to LDs and controls will allow us to ascertain events by the same approach in both LDs and controls. Simultaneously obtaining outcomes for both groups the same way will avoid a differential ascertainment bias. Further, the granular long-term follow-up of REP controls and the UMN LD program will provide independent sources for validating the timing and onset of self-reported outcomes on the new survey. Thus, we will be able to provide the most complete and detailed information on long-term LD outcomes as compared to a well-matched healthy control cohort.Findings from this study will be disseminated through peer-reviewed journals, conference presentations, and targeted dissemination/presentation to advocacy and stakeholder groups. To translate our findings into an understandable format for LDs and their care team we will develop a user-friendly long-term risk calculator. This freely available, interactive online calculator or app will allow candidate donors (and their providers) to estimate their risk of each outcome (including intermediate outcomes) at different time intervals with versus without kidney donation.The MARKD study will provide the best data, to date, on the attributable risk of kidney donation. The data will inform prospective candidates of the long-term risks (if any) of kidney donation; and inform best practices in long-term clinical follow-up, as well as the design of long-term health maintenance/surveillance of donors.Below is the link to the electronic supplementary material.Supplementary Material 1Supplementary Material 2Supplementary Material 3


To find the incidence of various complications of therapeutic plasma exchange (TPE) in ICU admitted children and to determine their association with age, gender, blood group and diagnosis of the patients.In this observational study, data of 24 patients who underwent 125 sessions of TPE was collected from the Pediatric Intensive care unit (PICU) and Hematology department of The Children’s Hospital, Lahore from December 2020 to November 2021. Age, gender, blood group, indications and complications observed during and after the TPE procedure were documented on a pre-designed proforma. The data was analyzed by using SPSS version 23. Quantitative variables were presented in the form of mean and standard deviation. Qualitative variables like gender, blood groups, indications and complications of plasmapheresis were presented as frequency and percentage. Chi square test was applied for comparison of variables.Among the 24 patients, 45.8% were of age group five to ten years with mean age of 7.58 years± 2.04 years and male to female ratio of 0.84:1. Guillain-Barré syndrome (GBS) and Neuromyelitis Optica spectrum disorder (NMO-SD) were the most prevalent among the patients who underwent TPE. Most common complication was hypotension (44.9%), others were febrile reactions (11.6%), unstable vital signs (14.5%) and allergic reactions (24.6%). Blood group, clinical condition and diagnosis of the patient showed significant association with the incidence of TPE related complications.The majority of problems caused by TPE are considered to be minor. Sudden fall in blood pressure, pruritus, urticarial rash and fever are the common adverse consequences among pediatric patients. Blood group and diagnosis of the patient can determine the development of such complications during plasmapheresis procedure. Treatment with therapeutic plasma exchange (TPE) involves removing plasma from the blood and replacing it with an isotonic fluid  in order to maintain the patient’s proper oncotic pressure.2Three to five different exchange operations are commonly included in a TPE course, which is performed every 24 to 48 hours. Exchange-dependent kinetics explain why this happens in the first place. Depending on the hematocrit, one to two TPV  equivalents are replaced over the course of several hours in each exchange. Most immunoglobulin G-class autoantibodies are found in tissues and interstitial fluid (the “third space”), which means that numerous exchanges are frequently necessary because only about 30% of the total quantity in the body is contained in the intravascular space.3When it comes to the technical aspects of TPE like establishing a vascular access and volume distribution, children may be at greater risk than adults due to this therapy’s inherent principles. Hemodynamic instability, coagulation problems, and electrolyte imbalances are more common in critically sick patients, making the procedure less effective.TPE outcome in different pediatric disorders have been explored in previous studies.It was an observational study, conducted in PICU and Hematology department of The University of Child Health Sciences, The Children’s Hospital, Lahore from December 2020 to November 2021. The study was approved by the hospital review committee (Reference No. 2020-172 dated 21/11/2020). A total of 24 children of both genders who had 125 sessions of TPE in total, were enrolled after taking written informed consent from the parents/guardians. Patients whose parents refused to participate in the study or rejected the TPE treatment and/or those who had any contraindication of the procedure were excluded.Age, gender, blood groups (ABO and Rh-D blood group system) and indications of plasmapheresis , Guillain-Barré syndrome (GBS), Guillain-Barré syndrome (GBS) with Autonomic Instability, Neuromyelitis Optica Spectrum Disorders (NMOSD) were noted. Blood grouping was done by tube method, using antisera A, B, & D (Lorne UK) for forward grouping and A cells, B cells, and O cells for reverse grouping.The procedure was observed by a trained ICU nurse, pediatric resident and a hematologist. The vital signs of all patients were noted before, during and after the procedure and any complication during and after the TPE method were also documented on a pre-designed proforma.The collected data was entered and analyzed by using SPSS version 23. Quantitative variable like age, was presented as mean and standard deviation. Qualitative variables like gender, blood groups, indications and complications of plasmapheresis were presented in the form of frequency and percentage. Chi square test was applied for the comparison between qualitative variables and p value <0.05 was taken as significant. Effect modifiers like age, gender and indications of plasmapheresis, were controlled through stratification.In this study, 24 patients admitted in PICU were included who had 125 sessions of TPE in total. Among the participants, 45.8% (n=11) were male and 54.2% (n=13) were female with male to female ratio of 0.84:1. Majority of the patients (45.8%) were between five to ten years of age with mean age ± 2SD of 7.58 years± 2.04 years.Various indications shows in Incidence of Adverse events among complicated TPE sessions (n=69 )are shown in Stratification of the TPE shows in Therapeutic plasma exchange (TPE) removes and replaces plasma to treat a range of disorders. TPE eliminates pathogenic chemicals , improving health. The method is utilized in practically all sections of medicine for a variety of disorders, some of which might be life-threatening, and consequences that may not otherwise be considered morbid. TPE should be performed only by experienced staff in specialized centers to minimize the risk of complications.6In our study TPE was performed mainly for the neurological conditions among which Guillain-Barré syndrome (GBS) was the most dominant one encompassing more than half of TPE sessions performed. Other disorders included NMO-SD, autoimmune encephalitis, GBS with autonomic instability, CIDP and NMO-SD with Lower stem transverse myelitis (LSTM). It can also be done for other diseases as well like renal diseases and sepsis.The most common indications reported in the World apheresis registry are neurological disorders.11We found hypotension and urticaria to be the common TPE related complications. The hypotension was not life-threatening and did not require vasopressors. As it is evident from the results that gender and age were not of any significance in the occurrence of the complications. Mokrzycki and Kaplan et al., found urticaria to be the most prevalent adverse response to plasma exchange operations while our study showed around 17 cases (24%) who suffered from urticarial rash.Our findings are consistent with those of Haque et al., where they showed that hypotension was most frequent finding and it was not proved to be life threatening.20Allergic reactions in our study were reported of mild intensity. However, Huestis et al.We found Blood group B Rh-D positive and O Rh-D positive to be associated with TPE complications. But since these blood groups are the most prevalent one among our population so further case-control studies required for this purpose to establish reliable and accurate association.included patient selection bias, as majority of patients with neurological disorders were selected. The study was time- bound so only immediate complications were included. Long-term follow-up of these patients who underwent TPE procedure can provide a better information regarding clinical outcome. Multicenter research is also recommended to investigate further the patient and procedure related factors, in context of complications and to provide reliable predictors of such adverse reactionsTPE is a therapy for the purification of blood that is mostly risk-free for use in children. The majority of problems caused by TPE are considered to be minor. Sudden fall in blood pressure, pruritus and urticarial rash are the most often seen consequences. Patient’s diagnosis, current clinical state and blood group play an important role in determining development of complications during the procedure.Hypotension is a major complication and must be dealt cautiously and timely to avoid any life threatening conditions but overall TPE is a comparatively safer and life-saving procedure to be performed in PICU especially when performed earlier in the course of disease.TF: Designed & Contributed in manuscript writing. She is also responsible for the accuracy of the work.NiS: Collection & assembly of data.MS: Data Collection, Manuscript writing.NS: Review of manuscript and references.


Acute aortic dissection (AAD) is a severe cardiovascular disease characterized by rapid progress and a high mortality rate. The incidence of acute aortic dissection is approximately 5 to 30 per 1 million people worldwide. In clinical practice, about 35% of AAD patients are complicated with acute lung injury (ALI). AAD complicated with ALI can seriously affect patients’ prognosis and even increase mortality. However, the pathogenesis of AAD combined with ALI remains largely unknown. Given the public health burden of AAD combined with ALI, we reviewed the anesthetic management advances and highlighted potential areas for clinical practice. Acute aortic dissection (AAD) is a severe cardiovascular disease characterized by rapid progress and a high mortality rate. It seriously endangers the safety of people. The incidence of AAD is approximately 5 to 30 per 1 million people annually worldwide , 3. WithSeveral classification systems have been established for AAD. Among them, Stanford and DeBakey are the most used. Aortic dissection can be divided into Stanford type A, involving the ascending aorta, and Stanford type B, confined to the descending aorta. DeBakey type I is defined as the entire aorta affected; DeBakey type II confines the ascending segment; DeBakey type III confines the descending segment. Acute aortic dissection type A is a highly lethal acute aortic syndrome, with in-hospital mortality of 15–38% . In mostA recent study suggested that inflammation and coagulation are involved in AAD combined ALI , 10. EndNuclear factor kappa-light-chain-enhancer of activated B cells ( NF-κB) can regulate the transcription of several encoding proinflammation cytokines genes and accelerates lung dysfunction . NF-κB sInterleukin-22 (IL-22) is a protective inflammation factor that plays a critical role in the pathogenesis of autoimmune diseases and anti-apoptosis. Moreover, IL-22 is a member of the IL-10 family, which has protective effects on animal models with ischemia-reperfusion injury in the lung . The JAKHigh-mobility group box 1 (HMGB1) is a nuclear nonhistone protein crucial in initiating and maintaining inflammation . The recAmong AAD patients, the most dangerous risk is hypertension. Almost 75% of patients have a history of hypertension, especially poorly controlled. Other risk factors include trauma, drugs, smoking history, and genetic disorders  . AccordiObese patients are more predisposed to develop ATAAD complicated ALI . ObesityFurthermore, the interaction between genetics and the nongenetic-environment is involved in the progression of ALI . Recentl2/FiO2 ≤ 200 mmHg with positive end-expiratory pressure or continuous positive airway pressure ≥ 5 cmH2O; ALI was introduced using the same criteria but with less-severe hypoxemia  [It is crucial for AAD patients to quickly confirm the diagnosis, clarify the classification, and locate the intimal injury site. ATAAD can be misdiagnosed as myocardial infarction, acute coronary syndrome, or cardiac arrest of unknown reasons in emergency department . It is e00 mmHg) . Additio00 mmHg) . The sco00 mmHg) . In rece00 mmHg) , 42. As A pre-test probability assessment of the risk scores of aortic dissection detection (ADD-RS) might improve AAD diagnosis and decrease the misdiagnosis rate –45. ADD-Considering the high mortality rate, a study suggested that the time from symptom onset to surgery in patients with ATAAD should not exceed 10 h . When coFor patients with ATAAD, initial management aims to control blood pressure and pain, which can limit the false lumen propagation . Blood p2/FiO2 < 200 mmhg, keeping PaO2 55–80 mmHg or SpO2 88-95% and pH ≥ 7.25 might lead to improved outcomes [Both inflammation and coagulation are involved in ATAAD-complicated ALI. Coagulation disorder is usually associated with low coagulation factors and high D-Dimer in ATAAD patients. Moreover, secondary fibrinolysis caused by ATAAD can worsen ALI . Therefooutcomes .Assessment of pulmonary risk is essential for AAD-complicated ALI patients. A series of predicting risk indexes for evaluating postoperative respiratory failure have been made based on emergency surgery, a history of smoking, and chronic obstructive pulmonary disease . ArteriaSwift surgical treatment is essential to repair AAD. Complex monitoring is currently suggested in clinical practice, including invasive arterial blood pressure, central venous pressure, nervous system, depth of anesthesia, and regional cerebral oxygen saturation. Transesophageal echocardiography has an advantage in diagnosing acute intraoperative hemodynamic instability. Therefore, it can be used to evaluate aortic dissection-related cardiac complications, which can lead to, or aggravate, acute respiratory distress syndromes, such as aortic regurgitation, proximal coronary artery involvement, presence of pleural effusion, and compression of pulmonary artery . TEE canThe primary principle of induction is sustaining a stable circulation. Perioperative aspiration prevention is also important during emergency cardiac surgery. Gastric ultrasound accurately identifies and measures gastric volume and contents, qualifying a safe airway assessment and minimizing aspiration risk . For hemVolatile and injectable anesthetics can be employed in cardiovascular surgery. For patients with stable hemodynamics, totally intravenous anesthesia(TIVA) has fewer side effects such as nausea and vomiting, and a lower risk of developing malignant hyperthermia. Pretreatment with volatile agents has cell-protective effects through intracellular signaling pathways, gene expression, and changes in mitochondrial function in the animal models, and it protects against ischemia-reperfusion injury. Volatile agents can also reduce myocardial infarction . HoweverPerioperative lung injury is a common complication in patients undergoing Sun’s surgery. Thus, conservative fluid management is essential. Fluid overload may aggravate lung injury, increasing ICU stay and mortality risk. Gelatin and other colloids have been used in heart surgery to enhance plasma volume. However, their effects on renal function are debatable. A recent report showed that 4% succinyl gelatin administration was not associated with an increased risk of kidney injury in cardiac surgery compared to the crystalloid-only group . Fluid mFor preoperative ALI, we suggest a low-tidal volume protective ventilation mode (6–8 mL/kg predicted body weight) to reduce the incidence of ventilator-induced lung injury. Permissive hypercapnia is a lung protective ventilation strategy widely used in recent years. A recent prospective investigation in elective cardiac surgery patients demonstrated that maintaining the PaCO2 at 46–60 mmhg could increase cerebral blood flow and improve the cerebral oxygen supply/consumption balance . CardiacMechanical ventilation remains the mainstay management for AAD- complicated ALI patients. However, it can bring potential injuries to ALI patients. The underlying mechanism of lung injury caused by ventilation can be divided into volutrauma and aelectrauma, which can aggravate the leakage of plasma-derived fluid and proteins into the mesenchyme of the lung . Thus, a20) was lower than the best PEEP by PaO2/FiO2 (11.9 ± 4.7 cmH20). They also suggested that the best method for PEEP should affect patient outcomes [T) < 8 mL/kg ideal body weight, modified driving pressure (peak inspiratory pressure - PEEP) < 16 cmH2O, and PEEP ≥ 5 cmH2O, and demonstrated that it is the driving pressure associated with the lower likelihood of PPCs [Driving pressure is defined as plateau pressure (Pplat) minus PEEP, representing the stress and strain on the lung. For patients undergoing general anesthesia, intraoperative high driving pressure is associated with more postoperative pulmonary complications . A prospoutcomes . A recen of PPCs .Mechanical power is the energy per unit time generated by ventilation applied to respiratory system . A retroIntraoperative lung recruitment has been proposed since the 1960s. It is defined as an inspiratory hold with 40 cmH2O of inspiratory pressure for 20–30 s to prevent atelectasis. However, we should be cautious about its effects on the left ventricular end-diastolic and cardiac output. A recent study on patients undergoing on-pump cardiac surgery proved that intensive alveolar recruitment procedures (continuous positive airway pressure maintained at 30 cmH2O for 30 s) would be more suitable for patients with hypoxemia or significant lung atelectasis rather than a preventive approach . They al2) management, a high oxygen concentration might lead to absorption atelectasis and even aggravate lung injury. Besides, moderate hyperoxia (50–80% FiO2) might reduce the incidence of surgical infections. However, more studies are required to determine the optimum FiO2 to prevent infections and atelectasis in cardiac surgeries [The debate on ventilation during CPB is still going on. An argument states that it can improve gas exchange and oxygen index. A prospective randomized trial showed that maintaining ventilation during CPB cannot reduce PPCs in cardiac surgery patients . Anotherurgeries . Athough2O, driving pressure of 15 cmH2O, respiratory rate of 15/min, inspiratory time of 1.5 s, and FiO2 of 40%) in the postoperative phase is associated with fewer PPCs, shorter ICU lengths of stay, lower use of supplement oxygen, and extended noninvasive mechanical ventilation [2O over 30 s; second step: change the ventilator mode to pressure control with an inspiratory pressure of 20 cmH2O for 30 s; third step: decrease the PEEP to 10 cmH2O over 2 min [An optimal postoperative management schedule might benefit preoperative ALI patients. For AAD-complicated ALI patients, postoperative pulmonary complications after cardiac surgery can increase the mortality in the ICU. A more intensive alveolar recruitment strategy  is a vasodilator, especially for pulmonary hypertension patients. It can enhance arterial oxygen, regulate inflammatory-induced microvascular injury in the lung, and decrease the need for ventilation. A recent study showed that NO could reduce pulmonary and systemic neutrophils and pre-inflammatory factors in lung injury in a rodent ARDS model . DexmedeThe use of neuromuscular blocking agents (NMBA) in ARDS adults is debatable. In ARDS patients undergoing mechanical ventilation, NMBA might improve oxygenation and decrease mortality. A multicenter prospective trial showed that using NMBA in early severe ARDS with low tidal volume ventilation could improve the adjusted 90-d survival . A recen2O PEEP can minimize lung injury, improve gas exchange, and not affect hemodynamic stability [Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is another essential tool to treat ALI. VV-ECMO has been increasingly used in ALI patients, especially for those whose conventional ventilation management fails to supply adequate oxygen exchange . Additiotability . However2R) can improve acidosis via CO2 clearing. ECCO2R combined with ultra-lung protective ventilation, driving pressure, titrating PEEP, or optimizing mechanical power might have more lung protective effects. A prospective study found that using ECCO2R and ultra-protective ventilation could mitigate respiratory acidosis in moderate ARDS patients [Extracorporeal carbon dioxide removal (ECCOpatients . HoweverAmong patients with preoperative ALI complicated with AAD, early and rapid assessment of ALI and guidance for early management results in lower mortality. Combining the detection risk scores of AAD could decrease the misdiagnosis rate, which should be validated in more prospective studies. Moreover, the recommendations regarding the treatments, and intervention strategies to better manage AAD-complicated ALI patients including ventilation mode, drug therapy, extracorporeal membrane lung need further investigation. Improving diagnostic skills, transfer system implementation and enhancing communication with departments may shorten the time from the onset to surgery in patients with ATAAD. Increased awareness might further aid AAD diagnosis. More randomized clinical trials are required to optimize the perioperative management.


Conclusions: Our results confirm the commonly accepted 20 min threshold for WI time, suggest less than 30 min ischemia time when using SAC, and support a ZI approach if safely performable to reduce the risk of postoperative AKI. Selecting an appropriate ischemia type for patients undergoing RAPN can improve short- and long-term functional kidney outcomes.Background: Acute kidney injury (AKI) after robot-assisted partial nephrectomy (RAPN) is a robust surrogate for chronic kidney disease. The objective of this study was to evaluate the association of ischemia type and duration during RAPN with postoperative AKI. Materials and methods: We reviewed all patients who underwent RAPN at our institution since 2011. The ischemia types were warm ischemia (WI), selective artery clamping (SAC), and zero ischemia (ZI). AKI was defined according to the Risk Injury Failure Loss End-Stage (RIFLE) criteria. We calculated ischemia time thresholds for WI and SAC using the Youden and Liu indices. Logistic regression and decision curve analyses were assessed to examine the association with AKI. Results: Overall, 154 patients met the inclusion criteria. Among all RAPNs, 90 (58.4%), 43 (28.0%), and 21 (13.6%) were performed with WI, SAC, and ZI, respectively. Thirty-three (21.4%) patients experienced postoperative AKI. We extrapolated ischemia time thresholds of 17 min for WI and 29 min for SAC associated with the occurrence of postoperative AKI. Multivariable logistic regression analyses revealed that WIT ≤ 17 min (odds ratio [OR] 0.1,  Partial nephrectomy is the recommended treatment for small renal masses and provides safe oncological results in the case of renal cell carcinoma . In compAcute kidney injury (AKI)—regardless of etiology—can aggravate preexisting or induce chronic kidney failure . AKI aftThe objectives of this study were to identify optimal ischemia time thresholds for WI and SAC during RAPN and to investigate the association of WI, SAC, and ZI, within the proposed time thresholds, with postoperative AKI.We retrospectively reviewed all patients who underwent RAPN for small renal masses at a tertiary referral center between 2011 and 2019. The Cantonal Review Board of Zurich approved the study protocol (no. 2017-01148). We elaborated this observational study according to the STROBE statement for cohort studies Data collection was based on the electronic case history and surgical video recordings. Patient characteristics collected to assess for potential confounders included patient age, gender, body mass index (BMI), the presence of arterial hypertension or diabetes mellitus, the presence of accessory arteries, Charlson Comorbidity Index, and baseline estimated glomerular filtration rate (eGFR).Patients who received marsupialization of benign cysts, bilateral or multiple RAPNs, or intraoperative conversion to open radical nephrectomy or partial nephrectomy were excluded. We further excluded patients with single kidneys or evidence of metastasis .The estimated glomerular filtration rate (eGFR) was calculated using the serum creatinine level according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula . AKI wasda Vinci® surgical system . Generally, we used a four-arm robotic system with a maximum of two accessory 12 mm trocars. The trocar number and sites were determined at the surgeon’s discretion. After dissection of the arteries, bulldog clamps were used to interrupt blood flow to selected arteries. Once the tumor was resected, we closed the renal parenchymal defect with two layers of sutures. First, the resection area was closed using an absorbable, monofilament suture with clips on both ends to tighten it for hemostasis. After this step, the early declamping of afferent arteries was pursued. Second, we placed absorbable braided sutures for renorrhaphy. Overall, four senior surgeons performed all operations. To ensure standardized surgical techniques in the department, a consensus was reached among the surgeons at the start of the robotics program and during regular staff meetings.All RAPN were performed either by the laparoscopic or retroperitoneoscopic approach using the The operating surgeon chose the ischemia type according to personal preference, based on the tumor characteristics, the vascular situation of the affected kidney, and the patient’s medical history. The used ischemia types were warm ischemia, selective artery clamping, and zero ischemia. Warm ischemia was defined as ischemia of the entire kidney by clamping all afferent renal arteries without remaining perfusion . By clamA senior radiologist reviewed the preoperative CT or MRI imaging for the confirmation of accessory renal arteries and verification of the used ischemia type. We individually reviewed all operations’ video recordings regarding the used ischemia type and time. Tumor complexity was assessed through the preoperative CT or MRI images using the R.E.N.A.L.  nephrometry score .2 test was used for continuous and categorical variables, respectively.We reported continuous and categorical variables using the median with interquartile range (IQR) and frequencies with proportions, respectively. For the comparison of patients’ baseline characteristics between subgroups, the Mann–Whitney U or χWe used STATA’s “cutpt” program to define optimal ischemia time thresholds for SAC and WI to predict the risk of postoperative AKI. This program integrates the Youden index and the Liu method to extrapolate cut-off points with optimal sensitivity and specificity. The Youden method maximizes the sum, whereas the Liu method maximizes the product of sensitivity and specificity. It further bootstraps the standard error to estimate the 95% confidence interval for the calculated threshold value.Univariable and multivariable binary logistic regression analyses were performed to investigate predictors for postoperative AKI. We created a multivariable model for the risk of postoperative AKI by including the extrapolated ischemia types of interest and all significant parameters from the univariable analysis. We calculated the receiver operating characteristic–area under the curve (ROC-AUC) to evaluate the model’s performance accuracy. The clinical net benefit of the model was assessed by decision curve analysis, which can be interpreted as a comparison between the proposed model and the model without ischemia types, giving the percentage of patients saved from AKI after RAPN within a certain threshold probability. Based on the proposed model, we generated a nomogram ready for clinical use to predict the probability of postoperative AKI.p-values ≤ 0.06 from the univariable Cox regression analysis were considered. All statistical analyses were conducted using STATA Version 16.0 . All tests were two-sided and a p-value < 0.05 was considered statistically significant.The association of AKI and its risk factors with long-term kidney function was assessed using Kaplan–Meier estimates and Cox proportional hazard regression models. The predefined ischemia types of interest and all significant parameters from the univariable Cox regression analysis were included in multivariable model 1. In multivariable model 2, all variables with Overall, 154 patients who underwent RAPN were included in the analysis . The medp < 0.001) (p < 0.001) : 13.3–20.7 min, < 0.001)  and 29 m< 0.001) , respect< 0.001) . Twenty-p = 0.033), zero ischemia , warm ischemia ≤17 min , and SAC time ≤29 min  were independently associated with the occurrence of postoperative AKI. The R.E.N.A.L. nephrometry score could not retain significance . The multivariable model provided high accuracy with an 84% AUC-ROC  with a significant long-term eGFR reduction  patients experienced a significant eGFR reduction. Cox proportional hazard regression models predicting a significant long-term eGFR reduction are displayed in eduction . None ofIn this retrospective analysis, we demonstrated that the choice of intraoperative ischemia type during RAPN has profound implications for the occurrence of postoperative AKI, which is one of the strongest prognostic factors for long-term functional outcome. Dependent of the used ischemia type, the ischemia time seems of paramount importance. When RAPNs were performed with ZI, WI below 18 min, or SAC below 30 min, the risk of postoperative AKI decreased by approximately 90%.When using the WI approach, we found that an ischemia time above 17 min best predicted the incidence of postoperative AKI. The optimal WI cut-off for the purpose of kidney function preservation has been debated for years and was initially suggested to be 30 min ,25. A laWe could further point out that SAC below 30 min is equally protective as ZI or WI below 18 min for the occurrence of postoperative AKI in comparison to WI above 17 min. To our knowledge, this is the first ischemia time cut-off proposed for SAC during RAPN. Selective artery clamping allows the partial ischemia of the kidney harboring the tumor and therefore better visualization in bloodless conditions during tumor resection, while other parts of the kidney are still perfused. Under these conditions, the pathophysiological mechanisms for the development of postoperative AKI are not completely clear yet, but it seems that selective ischemia affects the healthy renal parenchyma by inducing an inflammatory response in combination with renal ischemia–reperfusion injury and subsequent cellular damage . PreviouThirdly, we were able to demonstrate that the ZI approach produced comparable, tending to be slightly better, functional results to WI below 18 min and SAC below 30 min. This tendency can also be observed when inspecting our nomogram. The decisive advantage is that the surgeon is not limited in terms of the ischemia time and can fully avoid damage to healthy renal tissue due to ischemia. Whenever a resection needs more time due to the intermediate or high complexity of the tumor, the ZI approach should be pursued if complete tumor resection is safely feasible. Since its first description, ZI has been shown to be effective even in large and/or endophytic tumors ,37,38. HWhile most of the supporting evidence for the 20 min WI cut-off relates to its association with mid- to long-term kidney function ,27, our The natural course of AKI usually shows a return to the baseline eGFR, followed by a deterioration in eGFR influenced by the severity and duration of AKI as well as patient comorbidities . The proThe nomogram that was created could help in assessing the risk of postoperative AKI prior to RAPN. In patients with preexisting chronic kidney disease or a high risk of postoperative AKI, the surgeon can select the ischemia type that corresponds best to the complexity of the tumor. For tumors with low complexity, experienced urologists generally expect ischemia times below 18 min and can safely apply WI. For tumors with higher complexity, however, urologists need to decide whether a time-consuming hilar preparation to dissect the branches of the main renal artery to apply SAC is reasonable to gain more time for a challenging resection. If the surgeon has experience, ZI is another treatment option to prevent AKI in such cases. This nomogram, along with other published predictive tools, could provide assistance for the preoperative decision-making process to reduce the risk of postoperative AKI and thereby long-term kidney function loss according to given risk factors ,15.This study has several limitations, such as being single-center with a retrospective design and a small sample size. In addition, the RAPNs were performed by four different surgeons. Despite the institution’s efforts to standardize the surgical techniques, certain differences could have had a confounding influence on the results. However, all surgeons were experienced in partial nephrectomy. The ischemia type was performed at the surgeon’s discretion and therefore selection bias was evident. When looking at the kidney function, there are two main limitations. First, pre- and postoperative kidney function were assessed using serum creatinine levels and the CDK-EPI formula, which is more susceptible to confounders than renal scintigraphy. However, pre- and postoperative scintigraphy were not routinely performed at our department. Secondly, AKI was assessed using serum creatinine levels but not urine output criteria (RIFLE) due to a lack of postoperative data. This might have contributed to missed events of AKI. Furthermore, we were unable to account for the extent of remaining renal perfusion caused by the various selective clamping techniques used, which could have introduced additional bias on its effect. Finally, our nomogram as well as our thresholds for the ischemia time require external validation through large prospective studies before implementation in clinical practice.The ischemia type and time during RAPN are of paramount importance for the short- and long-term preservation of renal function. Our analysis confirms the commonly accepted 20 min threshold for WI time, supports the ZI approach if safely performable, and suggests less than 30 min ischemia time when using SAC. We could further re-affirm the detrimental effect of postoperative AKI on long-term renal function. Our nomogram could help surgeons to individually estimate the risk of postoperative AKI and select the optimal ischemia type according to patient and tumor characteristics. External validation and large prospective studies are needed to validate our recommendations and extensively investigate the associations with given preoperative risk factors.


Background and aim: Aldosterone-renin ratio (ARR) is an important screening tool for the assessment of primary aldosteronism as a cause of secondary hypertension. This study aimed to measure the prevalence of patients with elevated ARR among samples of Iraqi patients with hypertension.Methods: A retrospective study was conducted at Faiha Specialized Diabetes, Endocrine and Metabolism Center (FDEMC) in Basrah during the period of February 2020 to November 2021. We evaluated the records of patients with hypertension whom were screened for endocrine cause, and an ARR cut-off equal or more than 5.7 was considered elevated.Results: Of the total 150 patients enrolled, 39 (26%) of them had an elevated ARR. No statistically significant association for the elevated ARR with age, gender, BMI, duration of hypertension, systolic and diastolic blood pressure, pulse rate, and presence or absence of diabetes mellitus or lipid profile.Conclusion: High frequency of elevated ARR was seen in 26% of patients with hypertension. More studies need to be conducted in the future taking larger samples. Primary aldosteronism (PA) is defined as non-suppressible aldosterone secretion causing hypertension, which was regarded as the most common cause of secondary (endocrine) hypertension -4. The cPrevalence of elevated ARR varies from region to region, ranging from 1% to 30% in different pieces of literature and this depends on the population being studied, degree of blood pressure elevation, prospective or retrospective data, and type of test used -14. In tStudy designA retrospective study was conducted at Faiha Specialized Diabetes, Endocrine and Metabolism Center (FDEMC) in Basrah. We collected data registered from the period of February 2020 to November 2021. Data collectionThe collected data include recorded ARR of patients with hypertension, and a cut-off equal to or more than 5.7 was considered elevated. One hundred fifty patients with hypertension were enrolled in this study. The other parameters retrieved were age, sex, body mass index (BMI), systolic and diastolic blood pressure (BP), pulse rate at the time of ARR measurement, duration of hypertension, creatinine, potassium level, and random lipid panel. Venous blood was drone while patients were seated for 15 minutes and not fasting.Inclusion and exclusion criteriaThe inclusion criteria included patients with age between 3 and 18 years, both male and female, and patients with hypertension fulfilling the 2016 Endocrine Society criteria for screening of PA [Biochemical analysisDirect renin concentration (DRC) measured by Renin ELISA  (reference range: 7.54-42.3 ng/L). Plasma aldosterone concentration (PAC) measured by Aldosterone ELISA  (reference range: 1.3-23.1 ng/dL). The ARR is equal to PAC/DRC with a cut-off of ARR < 5.7 considered normal . Serum pStatistical analysisThe data was analyzed using Statistical Package for Social Sciences version 28.0 for  as follows: continuous variables were summarized as mean value ± standard deviation and categorical variables were summarized as percentages and frequencies. Chi-square (X²) test was used to study the correlation between categorical variables, while the independent Student's t-test was used to study the correlation between continuous variables and categorical variables. We adopt the two-tailed probability values with p≤0.05 to be statistically significant.The general characteristics of the study patients in form of age, gender, BMI, presence or absence of diabetes, and duration of hypertension are summarized in Table In Table This study looked at the frequency of elevated ARR among a cohort of Iraqi patients with hypertension matching screening criteria for secondary endocrine hypertension namely primary aldosteronism. FDEMC is a tertiary care clinic, and hence the screened hypertensive population had a high pretest probability of having elevated ARR. We found that 26% of the studied patients had elevated ARR, and those patients with elevated ARR must then undergo confirmatory tests to establish or exclude PA to avoid future cardiovascular risks and to optimize their blood pressure control. In comparison with this study, Algün et al. in Turkey conducted screening for elevated ARR in a referring tertiary center and found that ARR was elevated in 17.4% of the studied patients, which is nearly similar results to our study findings despite that Algün et al. conducted more confirmatory tests to confirm the diagnosis of PA , while GThis was supported by studies across Europe where Hannemann et al. in Germany found that the total number of elevated ARR was 7% in population-based study . While iThe current study found a poor correlation between diabetes and elevated ARR, a similar result to Loh et al. despite they used confirmed PA and found no relation between the presence or absence of diabetes . In compOther parameters in this study, such as sex, age, lipid profile, systolic and diastolic BP, pulse rate, and duration of hypertension, were all studied and were found to be statistically non-significant and this may be due to the small sample size and the study not powered to study these parameters.LimitationsFirst, the study sample showed high prevalence of elevated ARR because of referral center bias and single center. Furthermore, the center received all difficult hypertension cases from Basrah, Iraq, for evaluation of ARR. Second, the current use of anti-hypertensive medications might over or underestimate the ARR value. Elevated ARR is common in Iraqi patients with hypertension (26% of patients) matching screening criteria. This could not reflect the true frequency of high ARR ratio due to study limitations. More studies need to be conducted in future including larger samples and collecting records from both tertiary centers and primary care centers.


Patients with IE more frequently had positive blood cultures more than 12 h after the first draw . There was a tendency to associate community-acquired bacteremia and to that all blood culture bottles obtained were positive with an increased risk of IE . Attributable mortality to infection was higher in patients with IE relative to all other patients . The multivariable analysis included having valve prosthesis and persistent bacteremia for more than 12 h. Both were independently associated with IE: valve prosthesis OR 38.6  and persistent bacteremia OR 2.6 . In conclusion, a high percentage of cases of CoNS bacteremia may be due to IE. Some of the variables related to a higher risk of IE, such as having a valvular prosthesis or presenting positive blood cultures for more than 12 h, should lead to rule out or confirm the presence of IE by performing echocardiography.Coagulase-negative staphylococci (CoNS) are currently considered typical microorganisms causing infective endocarditis (IE) in patients with prosthetic valves. The objective was to determine variables associated with IE in patients with CoNS bacteremia. We performed an analysis of the clinical characteristics of patients with CoNS bacteremia admitted to a university hospital in Madrid (Spain) from 2021 to December 2022 according to the occurrence of IE. This study is an evaluation of a bacteremia registry. During the study period, 106 patients with CoNS bacteremia were detected. In 85 patients an echocardiogram was performed during hospital admission to rule out IE. Among them, 12 episodes were detected that met IE criteria (14.2%). Of the 6 patients with heart valve prostheses, 5 patients (83.3%) had IE ( The aging of the population and the increase in invasive diagnostic and therapeutic procedures has led to an increase in the number of healthcare-associated IE cases1. One of the main pathogens in these cases are coagulase-negative staphylococci  and persistent bacteremia OR 2.7 .Table To calculate a risk score, the following variables were considered: valve prosthesis, community-acquired bacteremia, bacterial growth in all bottles obtained, persistent bacteremia for more than 12 h after the initial blood culture. We assigned points to each variable according to the logistic regression result: valve prosthesis (4 points), community-acquired bacteremia (2 points), growth in all blood culture bottles obtained (2 points), positive blood cultures separated by more than 12 h (1 point). The score scores were based on beta coefficients obtained using a one-step multivariate logistic regression model whose variables are shown in Table p = 0.217). The score showed a very good discrimination, with an area under the ROC curve of 0.87  and the marked association of this infectious complication with having a heart valve prosthesis.15. Unfortunately, CoNS frequently contaminate blood cultures because they are normal constituents of skin flora15. However, our results suggest that IE should be considered in patients with risk factors for this complication. Within CoNS, S. epidermidis was the most frequent cause of IE, as observed in other studies16. A slight tendency for S. epidermidis to cause IE and S. hominis to cause bacteremia without endocarditis was observed . This approach is similar to that is being studied for bloodstream infections caused by other bacteria that usually cause IE, including This study has several important limitations. Firstly, it is a retrospective study in a single hospital with a limited number of patients. These characteristics may limit the generalizability of the results. Secondly, we should point out that both the number of blood culture bottles and the time at which they were obtained during the follow-up of the patients showed some differences between them, which may have influenced the validity of the results obtained. In addition, the small number of cases of endocarditis has also reduced the number of variables to be considered in the multivariable analysis, which may have prevented the identification of independent variables associated with the risk of IE. Finally, t should also be noted that the characteristics of the study only allowed us to obtain the score for calculating the risk of endocarditis based on the result of the univariate analysis. Nevertheless, we consider that this work could be a starting point to try to establish more solidly the risk factors for endocarditis in patients with CoNS bacteremia.In conclusion, our study demonstrates that a high percentage of cases of CoNS bacteremia may be due to IE. The fact that the patient presents some of the variables related to a higher risk of IE, such as having a prosthetic valve, should prompt us to rule out or confirm the presence of IE by performing imaging tests such as echocardiography. Future studies should confirm the variables most strongly related to the risk of IE in patients with CoNS bacteremia.


Mounting evidence indicates that the gut microbiome (GMB) plays an essential role in kidney stone (KS) formation. In this study, we conducted a systematic review and meta-analysis to compare the composition of gut microbiota in kidney stone patients and healthy individuals, and further understand the role of gut microbiota in nephrolithiasis.Bacteroides  and Escherichia_Shigella , and a lower abundance of Prevotella_9 . Qualitative analysis revealed that beta-diversity was different between the two groups (P < 0.05); Ten taxa  helped the detection of kidney stones (P < 0.05); Genes or protein families of the GMB involved in oxalate degradation, glycan synthesis, and energy metabolism were altered in patients (P < 0.05).Six databases were searched to find taxonomy-based comparison studies on the GMB until September 2022. Meta-analyses were performed using RevMan 5.3 to estimate the overall relative abundance of gut microbiota in KS patients and healthy subjects. Eight studies were included with 356 nephrolithiasis patients and 347 healthy subjects. The meta-analysis suggested that KS patients had a higher abundance of There is a characteristic gut microbiota dysbiosis in kidney stone patients. Individualized therapies like microbial supplementation, probiotic or synbiotic preparations and adjusted diet patterns based on individual gut microbial characteristics of patients may be more effective in preventing stone formation and recurrence.The online version contains supplementary material available at 10.1186/s12866-023-02891-0. With an estimated 5-year recurrence rate of up to 50% , kidney Recent research has shown a growing connection between human diseases and the microbiota, and this connection is especially strong for the gut microbiome (GMB). GMB is formed by the trillions of commensal bacteria, fungi, archaea and viruses that are densely distributed in the gastrointestinal tract of mammals . DysbiosA close pathogenic association exists between the intestinal microbiota and kidney diseases (gut-kidney axis) like chronic kidney disease, acute kidney injury, glomerulonephritis, nephrotic syndrome, and IgA nephropathy, among others . PatientThis systematic review and meta-analysis were conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered at PROSPERO (No. CRD42022367346).Two members of our team independently searched scientific databases namely PubMed, Scopus, Medline, CINHAL, Web of Science, and the Cochrane Library from their inception through September 2022, in consultation with a sciences research librarian. Full search terms and an example of the search strategy can be found in  they were original research that examined the gut microbiota from kidney stone patients and compared that to controls; (2) they reported on the microbial community from stool samples. We excluded studies if (1) they were animal or in-vitro studies, commentaries, reviews, meta-analyses or editorials; (2) they detected microbiome from urine or stones samples; (3) they included populations having received chemotherapy within the previous year, or reporting antibiotic use recently.The primary outcome was differences in the abundance of gut microbiota between KS patients and healthy subjects at the genus level. The secondary outcomes were descriptions of the gut microbial diversity, potential detection capability and genetic functions in each study.P < 0.05) relative abundance at the taxonomic level of the gut microbiota between the groups. Disagreements were discussed until a consensus was reached. Alternatively, a third reviewer was able to fix them.The following information was extracted from the included articles by two independent reviewers: the first author's name, the publication year, the nation, the sample size, microbiota species, statistically significant  was used to assess the quality of the studies . The scaFor continuous outcomes, the relative abundance of gut microbiota, we collected the aggregate mean, standard deviation (SD) and standard error (SE) for quantitative synthesis to obtain the overall percentage of different microbial genera in KS patients and the controls. We also contacted the authors of original studies to obtain the data not available in the article. The relative abundance of gut microbes in kidney stone patients compared to healthy subjects was determined by calculating the difference in percentage of several genera between the KS and the control group. For the diversity, potential detection capability and genetic functions of gut microbiota, we only conducted qualitative synthesis because of the small sample sizes and the insufficient data.2 statistic was used to measure statistical heterogeneity between studies [P < 0.05 was considered statistically significant [All statistical analyses in this study were performed using the RevMan5.3 statistical software with the inverse-variance method. Forest plots represented the summary metrics. The I studies . Sensitinificant .P for begg’s test = 0.734)  in KS patients and 21.25%  in the control group , indicating that Bacteroides was more abundant in KS patients, the percentage of the KS group was 1. 65-fold higher compared to the control group. Sensitive analysis was done due to obvious heterogeneity , while in the control group, it made up 1.78% . The overall effect size was moderate and significant , showing that Escherichia_Shigella was more abundant in the KS patients, the percentage of the KS group was 2.47-fold higher compared to the control group. Sensitive analysis was done due to obvious heterogeneity , and in the control groups, it accounted for 10.65% . The overall effect size was moderate and significant , showing that Prevotella_9 was less prevalent in KS patients than in controls, the percentage of the KS group was 0.77-fold lower compared to the control group. Sensitive analysis was done due to obvious heterogeneity . Yuan et al. [P < 0.05), they found that in the KS group, the Simpson (P = 0.026), Ace (P < 0.01) and Chao (P < 0.05) indices were remarkably higher, while Shannon’s index was not significantly different from the control group (P > 0.05).The number (richness) and distribution (evenness) of taxa within a sample are measured by alpha diversity . Inconsin et al.  reportedP < 0.05).Beta diversity is a diversity indicator that shows how different or similar the microbial compositions of multiple samples are . Five arBacteroides, Phascolarctobacterium, Faecalibacterium, Akkermansia, and Lactobacillus . According to Tang et al. [Escherichia coli (AUC = 0.840) could be used to accurately categorize patients with nephrolithiasis. Xiang et al. [Flavobacterium, Rhodobacter, Gordonia were found useful in predicting kidney stones (AUCs ranging from 0.682 to 0.763). They found that using data from the three genera and four clinical indicators  together produced predictions that were more accurate than those made using just genus or clinical data, and random forest developed the most accurate model (AUC = 0.936).Three studies used receiver-operating characteristic curve (ROC) analysis to identify whether the gut microbiota could be used to distinguish between the two groups. Five genera of the gut microbiota were found to be biomarkers for calcium oxalate stones by Chen et al. : Bacterog et al. , P. aerug et al.  reportedP = 0.007), such as formyl-CoA transferase and oxalyl-CoA decarboxylase. Interestingly, these results were challenged by Suryavanshi et al. [P > 0.05).Four studies reported using shotgun sequencing, functional gene-targeted amplicon sequencing, or the bioinformatics software platform PICRUSt that the predicted genetic functions of KS patients were different from the controls. Through shotgun metagenomics, Ticinesi et al.  performei et al.  who obsei et al. , reporteP < 0.05). One study indicated that, compared to healthy subjects, a higher abundance of metabolic pathways related to inflammation, lipid metabolism, xenobiotics biodegradation and mineral metabolism were found in KS patients (P < 0.05) [Other different functions including glycan synthesis, energy metabolism, co-factors metabolism, and vitamins metabolism, of which protein families were downregulated in KS patients according to Suryavanshi et al. , whereas < 0.05) .Bacteroides and Escherichia_Shigella, and a lower relative abundance of genera Prevotella_9. We could not conduct meta-analysis of the altered distribution of other gut microbial genera due to insufficient data and limited overlap of findings. A clinical study reported that the expansion of Escherichia_Shigella in gut was related with the onset and response to immunosuppressive therapy of IgA nephropathy, and may serve as a promising diagnostic biomarker and therapeutic target [Escherichia trended to an inverse correlation with urinary citrate  [Bacteroides were found useful in detecting kidney stone disease [Bacteroides can produce urease [Bacteroides has a negative relationship with all short-chain fatty acids (SCFAs) [Prevotella negatively correlated with urine oxalate content [To our knowledge, this is the first meta-analysis of the gut microbiota composition of patients with kidney stones. There are consistent results indicating a characteristic gut microbiota dysbiosis in kidney stone patients. Identifying these dysbiosis characteristics may help in personalized clinical intervention. The results showed that, compared to healthy subjects, those with nephrolithiasis showed a higher relative abundance of genera c target . Escheri < 0.08) , which c < 0.08) . With th disease . Some Bae urease , which d (SCFAs) ; the abu content  and is p content . ModulatNumerous other clinical disorders, such as inflammatory bowel disease (IBD), obesity, type 1 and type 2 diabetes, have been linked to lower gut microbial diversity , 39. HowOxalobacter formigenes [Oxalobacter, Bifidobacterium, and Lactobacillus) may inhibit stone formation through extra-renal elimination of oxalate in the intestines and decreasing the oxalate concentration in plasma and urine [Advanced omics methods have enabled unprecedented levels of functional characterization and deep sequencing of gut microbial communities over the past ten years . The sysrmigenes , 33. It rmigenes , 43. Thermigenes , 45. Gutnd urine . Genes ind urine , 48, andnd urine –51, hypend urine . Glycan nd urine  by changnd urine , all of nd urine . OverallAkkermansia spp. and Lactobacillus spp. to promote the formation of calcium oxalate renal calculi [Prevotella enterotype to be associated with low nephrolithiasis risk dietary patterns characterized by a high-carbohydrate diet, while the Bacteroides enterotype was associated with high nephrolithiasis risk dietary patterns characterized by a high intake of animal protein [Lactobacillus and other health-promoting species [The metagenome-wide association study conducted by Zhernakova et al. has shown that inter-individual variations in gut microbiota composition are linked to a number of factors, including lifestyle, diet, diseases, and medications, of which dietary factors are the most crucial . Dietary calculi . Shikany calculi  reported protein . Several species –61, some species . TherefoOxalobacter formigenes, Lactobacillus, Bifidobacterium, Enterococcus, or other oxalate-lowering bacteria, alone or in combination, resulted in a reduction in urinary oxalate excretion in humans and rodents [Lactiplantibacillus Plantarum's ability to prevent kidney stone formation. Probiotic Lactiplantibacillus Plantarum N-1 prevented kidney stones caused by ethylene glycol by regulating the gut microbiota and improving intestinal barrier function [Lactiplantibacillus Plantarum J-15 corrected metabolic disorder, protected intestinal barrier function, and reduced inflammation to prevent stone formation [The above analysis provides us with further insights into the prevention and treatment of kidney stones. Restoring gut dysbiosis to maintain the balance of oxalate, citrate, and lipid metabolism may become a promising treatment for kidney stones. Antibiotics are proven to be effective in gut microbiota modulation by preventing pathogenic bacteria, but they also kill beneficial microbial communities and lead to antibiotic resistance in harmful bacteria . The use rodents . Miller  rodents  recentlyfunction , Lactiplormation . Synbiotormation . The saformation . In the ormation . It may This study is limited in that the number of studies and samples restricts the meta-analysis of more microbial species, and thus, more studies with larger sample sizes in this field are required to obtain more specific data on characteristic dysbiosis. In the included studies, only the effects of chemotherapy and antibiotics on intestinal flora were excluded; confounding variables like food and geography were not taken into account. Some of the included studies did not distinguish between primary and recurrent kidney stone formation and did not distinguish between the types of stones.Bacteroides and Escherichia_Shigella, lower relative abundance of Prevotella_9. The dysbiotic gut affects the formation of stone by regulating the host metabolism, particularly oxalate metabolism. Gut microbiota characteristics combined with clinical indicators help predict the occurrence and recurrence of kidney stones. High protein, tea, low carbohydrate, juice or fiber intake are risk factors for stone formation. Individualized therapies like fecal microbial transplantation, probiotic or synbiotic preparations and adjusted diet patterns based on the individual gut microbiota characteristics are promising therapeutic options.Kidney stone patients have a characteristic gut microbiota dysbiosis with higher relative abundance of Additional file 1:Supplementary Table 1. An example of the search strategy. Supplementary Table 2. Quality assessment of studies included for the meta-analysis. SupplementaryFigure 1. Sensitivity analysis of relative abundance of Bacteroides in subgroup of kidney stone patient vs control. SupplementaryFigure 2. Sensitivity analysis of relative abundance of Escherichia_Shigella in subgroup of kidney stone patient vs control. Supplementary Figure 3. Sensitivity analysis of relative abundance of Prevotella_9 in subgroup of kidney stone patient vs control. SupplementaryFigure 4. Funnel plot of studies included for meta-analysis.