In the multinomial model, lower sCD36 concentrations were associated with older age (p < 0.001), tobacco exposure (p = 0.006), T2D (p = 0.020), and a higher-platelets count (p = 0.004). However, in logistic regression models of diabetes, sCD36 showed only a weak association with T2D. The current findings show a weak association of circulating sCD36 with type 2 diabetes and no association with T1D. The aim of this study was to determine whether plasma concentrations of sCD36 (soluble CD36) are associated with the presence of type 1 or type 2 diabetes. Plasma levels of sCD36 were analysed in 1023 subjects (225 type 1 diabetes (T1D) patients, 276 type 2 diabetes (T2D) patients, and 522 non-diabetic control subjects) using an enzyme-linked immunosorbent assay (ELISA). Multinomial and logistic regression models were performed to evaluate associations with sCD36 and its association with diabetes types. There were no significant differences in sCD36 ( CD36 belongs to the class B scavenger receptor family, it is a transmembrane glycoprotein of 88-kDa expressed in a wide variety of cell types . CD36 reThe soluble form of CD36 (sCD36) was first described to be associated with metabolic syndrome in a small group of subjects: sCD36 was elevated in T2D patients compared with both lean (5-fold) and obese (2- to 3-fold) non-diabetic subjects . MoreoveThe aim of the current study was to assess whether the circulating concentrations of sCD36 are associated with diabetes, T1D or T2D, compared with a non-diabetic control group, all of them without previous cardiovascular events and free from chronic kidney disease. Taken together, the findings show a weak association of circulating sCD36 with T2D and no association with T1D. n = 225) and T2D (n = 276) were selected from two previous studies [n = 522) was selected from a population-based study in our region  [One thousand and twenty-three patients were recruited from the University Hospitals Arnau de Vilanova  and Germans Trias i Pujol  to participate in this study. Subjects with T1D ( T2D n = 6 were se studies . The con6 mg/dL) . AdditioBlood samples were collected in the fasting state, and blood tests were performed using standard laboratory methods . Urine tn = 64/522; T1D, n = 41/225; T2D, n = 24/276). Intra-assay and inter-assay precision coefficients of the ELISA assay were 4%–6% and 8%–12% respectively, as determined by the manufacturer. Plasma concentrations of human sCD36 were measured using a commercially available ELISA kit , in accordance with the manufacturer’s instructions. Appropriate dilutions of patient samples were measured in duplicates. Briefly, standards and samples were pipetted into the wells and incubated for 2 h on the plate shaker at room temperature (RT). After washing 4 times, a detection antibody was added and incubated for 2 h on the plate shaker at RT. Following washing 4 times, a streptavidin conjugated with Horseradish Peroxidase solution was added to the wells and incubated for 50 min on the plate shaker at RT and protected from light. After washing 4 times, 50 μL substrate solution (TMB-tetramethylbenzidine) was added to the wells and incubated for 20 min at RT protected from light. The colour development was stopped with 50 μL of stop solution. Absorbance was read at 450 nm using SpectraMax 340PC384 . The results were analysed using a log–log curve fit. The calibration was performed with recombinant human CD36 in the concentration range 1.95–250 ng/mL. For sCD36 concentrations lower than the detection limit, a value of 0.05 ng/mL was assigned , 1850× g and 3000× g (velocities used in other studies) [Due to the variability found in the concentrations of sCD36 in the published articles, we wanted to rule out that this was a consequence of differences in pre-analytical conditions. We designed an experiment to compare sCD36 assessed by ELISA  that included 96 samples from 14 volunteers. Plasma samples were processed at different centrifugation velocities: 1500× studies) ,30. Morestudies) .The analysis of CD36 by flow cytometry included 50 subjects, 22 T2D patients and 28 non-diabetic subjects. Peripheral blood samples were collected in the fasting state into vacutainers  containing EDTA. Erythrocytes were lysed with ammonium chloride , then the cells were washed with phosphate buffered saline (PBS), and incubated with monoclonal antibodies against CD36 , CD3, and CD14 . Thereafter, flow cytometric analysis was carried out on a Fortessa SORP flow cytometer , using sample acquisition and analysis software FACSDiva v6.2 . ® 480 PCR system using SYBR Green I Master . The primer pairs used were: forward primer 5′->3′ (GAGAACTGTTATGGGGCTAT) and reverse primer 5′->3′ (TTCAACTGGAGAGGCAAAGG). Gene expression values were normalized to the expression levels of glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The analysis of CD36 mRNA included the above-mentioned 50 subjects (22 T2D patients and 28 without diabetes). Erythrocytes were lysed with ammonium chloride (BD Pharm Lyse™), then the cells were washed with PBS and disrupted with QUIzol Lysis Reagent , and total RNA was extracted using the miRNA Mini Kit . Total RNA (1 µg) was reverse-transcribed using the Transcriptor First Strand cDNA Synthesis Kit . Each reaction was then amplified in a LightCyclert-test, ANOVA, the Mann–Whitney test, or the Kruskal–Wallis test. Regarding the differences in qualitative variables, this was assessed by the Chi-squared test or Fisher’s exact test. Tukey’s correction was used to account for multiple tests. Correlations were assessed by Spearman’s rank correlation coefficient. Associations between qualitative variables and sCD36 concentration were tested with the T test. Multinomial logistic regression models of sCD36 quartile were performed to study the variables associated with their levels, first quartile was used as reference. In these models, variables of the bivariate analysis with a p value <0.2 and clinical relevance were used. Logistic regression models of T1D versus non-diabetic and T2D versus non-diabetic were performed. For the models of diabetes, a non-diabetic age- and sex-matched group from the non-diabetic participants (n = 522) were selected for T1D (n = 314) and T2D (n = 247). In all models, the goodness-of-fit assumption was tested by the Hosmer–Lemeshow test. Logistic regression models were checked by receiver-operating characteristic (ROC) curves and DeLong’s test to correlated ROC curves. Estimates of odds ratios was reported with corresponding 95% confidence intervals and statistical significance was established as a p-value <0.05. The R statistical software, version 3.3.1, and SPSS software  were used for all of the analyses.Descriptive statistics of mean (standard deviation) or median (interquartile range) were estimated for quantitative variables while, for qualitative variables, absolute and relative frequencies were used. The differences between groups T1D, T2D, and control group, were assessed by Student’s A total of 1023 individuals, clinically well-characterised , were included in the study. In the overall study population, the mean age was 50 years, and up to 45.4% were men. The age in the different groups of participants ranged between 23 and 77 years in patients with T1D, between 40 and 75 years in patients with T2D, and between 27 and 84 years in the non-diabetic control group. There were significant differences among the three study groups for all studied variables, except for tobacco exposure. All the clinical characteristics can be found in p = 0.144). In head-to-head comparisons, concentrations of sCD36 were not different between non-diabetic and T1D subjects , non-diabetic and T2D subjects , or T1D and T2D . In addition, there were no significant differences in sCD36 levels divided in quartiles among the three groups (p = 0.062) (There were no significant differences in the median plasma concentrations of sCD36 among the three study groups (= 0.062) . p = 0.374), or T1D , median sCD36 concentrations were significantly higher in women in the non-diabetic group . In addition, sCD36 concentrations tended to be increased in T2D statin users  and tended to be decreased in T1D statin users .Furthermore, despite median, sCD36 concentrations were similar in women and men with T2D . Moreover, in the control group, age, BMI, systolic blood pressure, triglycerides, glucose, and HbA1c were negatively correlated. The number of platelets was positively correlated with sCD36  (p < 0.05). In the T2D group, sCD36 was not correlated with any of the analysed variables , systolic blood pressure, triglycerides, and haematocrit were negatively correlated with sCD36 ( < 0.01) . Finallyariables . p = 0.039) and in patients with dyslipidaemia (p = 0.048). Significantly lower sCD36 concentrations were found in T1D diabetes patients with tobacco exposure (p = 0.005). In non-diabetic subjects, significantly lower sCD36 concentrations were found in subjects with hypertension (p < 0.001), dyslipidaemia (p = 0.044), and statin users (p = 0.035)  .p = 0.014; Q3: OR = 0.980, p = 0.024, and Q4: OR = 0.967, p < 0.001), tobacco exposure with Q4 ; T2D with all quartiles of sCD36 ; and Q3 of platelets with the Q2  and Q4   was taken as a referent group and was compared with the other groups, defined as second (Q2), third (Q3), and quarter (Q4) quartile, respectively. In the whole group, the variables independently associated with sCD36 concentrations were: older age with all quartiles of sCD36  . p = 0.009), and Q4 , higher BMI with Q3 , and higher glomerular filtration rate (eGFR) with Q2   . p = 0.027) and Q3 , insulin treatment was associated with Q2 , treatment with oral anti-diabetic agents was associated with Q3 , and antiplatelet treatment was associated with Q3   was associated with Q2  . p < 0.001; Q3: OR = 0.260, p < 0.001; and Q4: OR = 0.299, p = 0.002), older age and higher triglycerides with Q4 , and Q3 of platelets with Q2 of sCD36 , Q2 of platelets with Q3 of sCD36  and Q3 and Q4 of platelets with Q4 of sCD36   .p = 0.003), the presence of hypertension , presence of dyslipidaemia , higher haematocrit , and the Q4 of platelets   a. The RO= 0.008) .p < 0.001), hypertension , dyslipidaemia , high BMI , higher haematocrit , Q2 and Q3 of platelets , and Q2 and Q3 of sCD36   b. The mo < 0.001 .Flow cytometric analysis was used to detect the expression of CD36 in circulating mononuclear cells from T2D patients and non-diabetic control subjects. In the recruited group, the mean age was 55 years, and up to 46% were men. No significant differences were found in the expression of CD36 scavenger receptor either in monocytes, or in leukocyte population between T2D patients and the non-diabetic group . Regardig, 1850× g, and 3000× g gave nearly identical results and a good correlation within each assay. Moreover, in the assays that compared samples with three, or without, freeze-thaw cycles, there were no differences in the results of the three different centrifugation forces, which were highly correlated (In the assay of sCD36, performed in healthy volunteers, we did not find differences in sCD36 among the different centrifugation forces or among the number of freeze-thaw cycles. Paired plasma samples prepared by 1500× rrelated . In the present study, we did not observe differences in plasma sCD36 concentrations between patients with T1D, T2D, and non-diabetic control subjects, all of them with normal renal function and free from advanced late diabetic complications, including macrovascular disease. Overall, there was an association between sCD36 plasma concentrations and cardiovascular risk factors such as hypertension, dyslipidaemia, tobacco exposure, age, sex, and BMI. In the current study, we measured most of the variables that have been previously described to be associated with sCD36. These factors included the use of several medications, age, sex, systolic and diastolic blood pressure, tobacco exposure, BMI, HDL, LDL, total cholesterol, triglycerides, haematocrit, haemoglobin, platelets, serum creatinine, blood glucose, and HbA1c. In addition, we have assessed for the first time, the contribution of all of these factors together in a large group of subjects with and without diabetes. Importantly, we found increased sCD36 in patients with T2D that had dyslipidaemia or that were antiplatelet users. As dyslipidaemia and the use of antiplatelet drugs is relatively frequent in T2D, this could have led to spuriously elevated sCD36 in previous studies in patients with T2D.Regarding the correlations between sCD36 concentrations and clinical variables, such as components of the metabolic syndrome among them insulin resistance, there is a large variability ,24,32,33To our knowledge, this is the first study that addresses the potential association of sCD36 with diabetes as a primary study objective. We did not find a clear association of sCD36 concentrations with T2D, the evaluation of the ROC curve shows that sCD36 does not contribute additional power to the predictive model. In fact, we did find a weak association of sCD36 with T2D, which may partly be due to the clinical and metabolic characteristics, among them waist circumference, which is an indirect measure of insulin resistance. In order to demonstrate that insulin resistance per se may be an associated factor to sCD36, direct measurements of insulin resistance should have been used. Regarding T1D, we found no association with sCD36. Patients with T1D showed younger age and had a high-frequency of hypertension and dyslipidaemia. Since sCD36 concentrations were not related to T1D, this may indicate indirectly that hyperglycaemia, which is a common feature in patients with either T1D or T2D, is not one of the main factors contributing to plasma sCD36 concentrations. Our findings are in line with some recent studies that found no association of sCD36 with diabetes or its associated metabolic disturbances in middle-aged subjects with metabolic syndrome , or patiCD36 signalling responds to ox-LDL, and on the one hand, reduces macrophage motility and probably induces the trapping of macrophages in the arterial intima, which promotes atherosclerosis. On the other hand, it induces chronic inflammation and contributes to insulin resistance common in obesity and dyslipidaemia, both associated to metabolic disorders ,38. HoweOur study has some limitations. First, although we adjusted for risk factors known to be associated with diabetes in our analyses, the possibility that some other confounding factors play a role may have been incompletely accounted for in plasma sCD36. Second, we did not validate our assay with tests from other manufacturers. Third, the cross-sectional design precludes conclusions about causality, and therefore prospective studies are needed to establish the usefulness of the sCD36 plasma concentration as a predictive factor for T1D and T2D. Finally, as we did not measure insulin resistance in the study subjects, this precludes the assessment of the impact of this metabolic variable on plasma sCD36 concentration.Circulating plasma sCD36 concentrations do not appear to be a biomarker of T1D or T2D. However, our study does not completely rule out the possibility that sCD36 may constitute a biomarker of cardiovascular events in diabetes and other populations. The follow-up of the cohorts with and without diabetes subjects may help to clarify this question.


CSF) shunt is the most common method of treating pediatric hydrocephalus. The Codman microadjustable valve (CMAV) is a CSF shunt constructed for children. The objective of the study was (a) to analyze complications after insertion of a CMAV shunt in hydrocephalic children, (b) to analyze complications after replacing a CMAV by an adult‐type Codman Hakim adjustable valve shunt (CHAV), and to (c) analyze the in vitro characteristics of the CMAV shunt and correlate the findings with the clinical performance of the shunt.Ventriculo‐peritoneal cerebrospinal fluid (CMAV shunt and later replaced by a CHAV shunt. We report on the complications that resulted from replacing the CMAV with the CHAV. We tested six CMAV shunts with or without an antisiphon device (ASD) in which opening pressure, resistance, sensitivity to abdominal pressure, ASD position dependency, and function were determined. The test results were correlated with the clinical performance of the shunt in the retrospective study.A retrospective study analyzed a cohort of hydrocephalic children who had received a CHAV without any further complications. A bench test of the CMAV was done to test whether the opening pressure was in agreement with the manufacturer's specifications. Our results were generally in agreement with specifications stated by the manufacturer.Thirty‐seven children  were identified. Within the first month after shunt placement, a total of 10 patients (27%) developed complications including infections, hygromas, and shunt dysfunction. Shunt survival varied from 1 week to 145 months. Over the 10‐year follow‐up period, 13 children had their shunts replaced, six of them with a CMAV with a CHAV was well tolerated by the patients. Bench test results were generally in agreement with manufacturers specifications. Replacing a CMAV with a CHAV in pediatric hydrocephalus patients can be accomplished safely.Replacing a  Shunt malfunction is a major problem in the pediatric population. A shunt malfunction can be subgrouped into shunt over‐ or underdrainage . Important features are the possibility of changing the opening pressure noninvasively to obtain the optimal opening pressure and if needed, treat over‐ or underdrainage  has a small size and is especially designed for use in children. According to the manufacturer, it has the same specifications as the Codman Hakim adjustable valve (CHAV). However, the smaller size could make it more difficult to locate the valve without radiological verification when the valve needs adjustment.The CMAV has been the first choice of shunt for children in our department since 1997 because of its smaller size compared with the CHAV. However, in those children that had their CMAV shunt revised with a CHAV, we often noted a problem of achieving an optimal opening pressure. This motivated us to do a retrospective quality assessment study of those children given a CMAV as their first shunt between 1997 and 2007, and in which we also analyzed risk, complications and clinical outcome in the cohort of patients that revised their CMAV shunt with a CHAV. We also wanted to test whether the problems we experienced could be due to the valve function and endurance of the CMAV. This question was addressed in an in vitro bench test of the CMAV in which we compared our results with those obtained in an earlier test of the CHAV . The medical records of all children, shunted with a CMAV as first shunt at the Department of Neurosurgery, Umeå University Hospital, between May 1997 and December 2007, were reviewed in terms of etiology, age at shunting, location of the ventricular catheter, adjustments, shunt survival, and reason for shunt revision. Shunt revisions in which the CMAV was replaced with a CHAV shunt, as well as the number of adjustments and any relevant clinical symptoms that may have resulted from the procedure were analyzed. Minor complications were defined as those that only needed an adjustment or antibiotic treatment. A serious complication was defined as a shunt that needed either a revision or a replacement. Postoperative complications were defined as those occurring within 1 month of surgery.2.2Six new CMAV shunts  with and without the corresponding ASD (Siphonguard™) were tested in vitro with the original proximal (14 cm) and distal catheters. We used an automated computerized experimental setup to evaluate the Codman Micro™ shunt with and without a corresponding ASD. Before the tests, all shunts were soaked in deaerated water for at least 24 hrs and simultaneously perfused with 0.33 ml/min deaerated water. The shunts and ASD were kept in a water bath between the different tests.2O, −22.1 mmHg) and the abdominal pressure , were obtained by leading the outflow from the shunt system to an overflow container with a constant water level.The setup for shunt testing has previously been described  regulated the simulated ICP according to a triangular waveform with duration of 60 min. The pressure was regulated between zero and the lowest multiple of 500 Pa (3.8 mmHg) resulting in a maximum flow exceeding 1.2 ml/min. The procedure was repeated a minimum of four times for each measurement. Measurements obtained during cycles disturbed by air bubbles were excluded.2O) for analysis of opening pressure and resistance with and without an abdominal hydrostatic component. One CMAV shunt with a performance setting of 30, 100, and 200 mm was tested with six different Siphonguards™ placed at +10 cm above and −30 cm below the ventricular catheter tip. The opening pressure and resistance were determined at all positions and with siphoning test at −30 cm.Every shunt was tested at its lowest, middle, and highest opening pressure . Paired t test was used to test for differences between groups. p ≤ 0.05 was considered statistically significant, and Bonferroni correction adjusting for multiple tests was used.Statistics was performed using JMP 10.0 . Values are expressed as mean ± standard deviation (33.1n = 11), preterm birth with postnatal hemorrhage (n = 11), aqueductal stenosis (n = 8), and other (n = 7). The shunt was inserted at the age of 1 day to 11 months (median 2 months). The shunt was inserted through a frontal burr hole in 23 children. An occipital or parietal approach was used in 10 and 3 children, respectively. For one child, data were missing regarding location of the burr hole. The setting at shunt insertion varied between 40 and 140 mm H2O (mean 78 mm) for 35 children. The most common settings were 60 mm H20 (7 patients) followed by 70 mm H20 (6 patients). For two patients, data were missing  had a CMAV inserted. In our material, we found that all the patients who received a CMAV were less than 1 year of age at the time of surgery, even though age <1 year was not exclusion criteria. The etiology for hydrocephalus was myelomeningocele (The follow‐up was at 12–145 months (median 45 months). During this period, six of the patients had died . The shunt survival varied between 1 and 145 months  were documented  there were difficulties. In nine of these cases, the placement of the valve had to be identified with X‐ray before adjustment, and in two other patients, there were several unsuccessful attempts before the valve was correctly adjusted.3.3n = 9; 24%) or received a new shunt  with a median 5 months to replacement (range between 1 and 113 months). The revision was due to proximal obstruction (n = 6), distal obstruction (n = 2), and a dysfunctional y‐connection (n = 1). Shunt replacement was due to infection , dysfunction of the valve , proximal obstruction , and distal obstruction . In five of these children, the shunt was exchanged to a CHAV, in four cases to a new CMAV. One of those CMAV shunts was later replaced with a CHAV. The other four patients had Strata (n = 1), standard Hakim (n = 1), or ventricular abdominal catheter inserted (n = 2).During the follow‐up period, of 145 months, a total of 22 patients (59%) of 37 underwent either a shunt revision in which a defective part of the shunt was exchanged  that did not respond to any subsequent changes in the opening pressure. Of the other patients, one developed a hygroma postoperatively, which was successfully treated with adjustment of the valve Table .3.4The opening pressure flow curves were generally continuous and smooth, but the closing was discontinuous in steps. The opening pressure correlated with the performance‐level settings. According to the manufacturer's specification, the opening pressure in the CMAV at the lowest, medium, and highest setting was 2.2, 7.4, and 14.8 mmHg, respectively. The opening pressure in vitro at the medium and highest settings was in accordance with the manufacturer's specification; however, at the lowest setting it was twice that provided by the manufacturer Table .p < 0.05) in the opening pressure  with an overall 10‐year incidence of infections of 16.2% (6/37). Other studies have documented infection rates of 10.9% (14/128), 6.2% (54/884) acute, and 7.4% (65/884) overall that required revision  patients outflow resistance is considered to be a positive predictor of improvement following shunt surgery. By lowering outflow resistance, shunt placement has a pronounced effect on the CSF dynamics (Malm, Lundkvist, Eklund, Koskinen, & Kristensen, The in vitro testing of the CMAV also documented that the variations in resistance were insignificant at the different performance settings with and without abdominal pressure. This is in agreement with previous findings in which the CHAV was tested in vitro with increasing opening pressures at higher performance settings, while the variations in resistance were insignificant in the range of 0.1–0.4 mmHg/ml/min (Arnell et al., 4.8Slit ventricles may be a complication after shunt placement and occur as a result of a hydrostatic siphoning effect when the patient is in upright position. Using a shunt with an ASD may help avoid this problem. To test this, we used a SiphonGuard in which the flow is regulated with two pathways, and which according to the manufacturer, the flow should be reduced by a factor of ten when only the second pathway is open. The siphoning test results of the CMAV documented an approximate 10‐fold increase in the resistance in the second way pathway of the SiphonGuard compared to the first way, which is in agreement with the manufacturer's specifications. Furthermore, the results are comparable to similar tests performed on the CHAV (Arnell et al., In testing the CMAV with SiphonGuard, we found higher opening pressures with increasing performance settings. The resistance, however, changed minimally between 5.4 and 5.6 mmHg/ml/min. This is in agreement with previous reports in which the CHAV was similarly tested. In that study, the opening pressure increased as the performance settings increased, while the resistance remained stable with a minimal variation between 5.7 and 5.9 mmHg/ml/min (Arnell et al., 5The CMAV was easy to handle, but the valve settings were difficult to identify at adjustments. The shunt survival rates were similar to other reported series. The replacement of a CMAV shunt with a CHAV shunt was generally well tolerated, but our cohort was small and caution in the assessment is therefore necessary. The CMAV had at the lowest setting an opening pressure which was double that reported by the manufacturer. The resistance was not dependent on the performance level or the abdominal pressure. Since the ASD did not affect either the opening pressure or the resistance in lying position, it may be an advantage to implant a shunt with an integrated ASD at the first shunt insertion also in pediatric patients. Bench test studies validate the correctness of the manufacturer's reports on the performance of the various shunt systems. This is, however, an in vitro study that limits our ability to draw conclusion about the in vivo functions of the shunt systems. Keeping this limitation of the study in mind, we nevertheless believe it is relevant to compare such data with clinical outcome studies as we have done in this report.All authors certify that we have no affiliations with or involvement in any organization or entity with any financial or nonfinancial interests.


Orthostatic hypotension (OH) is a common problem in older people. Although it is indicated that OH can be a marker of frailty there are no studies that evaluate this relationship in hospitalized patients. The aim of the study was to assess the prevalence of OH in geriatric ward patients and its association with health and functional ability characteristics and patients’ frailty status.A retrospective cross-sectional cohort study was conducted among patients aged 60 or over hospitalized in the geriatric ward.Patients’ medical records were analyzed and those with Active Standing Test (AST) results were included in the study.Orthostatic hypotension was defined by a drop in blood pressure of at least 20mmHg for systolic blood pressure and at least 10mmHg for diastolic blood pressure within 3minutes of standing up in AST. The database included sociodemographic characteristics, nutritional, functional and cognitive state, comorbidity and medical treatment. Frailty syndrome was diagnosed with Clinical Frailty Scale. Correlations with OH were counted and multivariable logistic regression models were built.416 patients were hospitalized in the study period and 353 (84.9%) were included, 78 (22.1%) men and 298 (84.4%) 75+ year-old. AST was not available in patients significantly more dependent in ADL and more frail. OH was diagnosed in 57 (16.2%) patients, significantly more frequently in men . The significant independent predictors of OH were lower diastolic blood pressure at admittance, nutritional risk in MNA-SF, Parkinson disease, α1-blockers, neuroleptics and memantine, and not the frailty syndrome diagnosed with Clinical Frailty Scale.OH affects a significant percentage of patients in the geriatric ward, although this problem may be underestimated due to limitations in the performance of AST in very frail and functionally dependent patients. Orthostatic hypotension (OH) is a common problem in older patients. It affects about 5–30% up to 80% of seniors, depending on the population studied as well as method and criteria of OH assessment used . Most stOH is closely associated with common chronic diseases, including hypertension, congestive heart failure, diabetes mellitus, and Parkinson’s disease. Adverse drug reactions of drugs used in Parkinson’s disease, hypertension, diabetic neuropathy, sleep disorders or depression may also lead to a sudden drop in blood pressure in upright position –10. It iAdverse consequences of OH independent of potential confounders include, among others, falls and fractures , 12, 13,The aim of the study was to assess the prevalence and clinical determinants of OH in geriatric in-patients, with special regard to its correlation with functional ability characteristics and frailty status. To the authors’ knowledge, there are no studies examining the relationship between OH and frailty syndrome in patients of geriatric wards.We retrospectively analyzed medical records of all consecutive patients admitted to the geriatric ward of the Hospital of the Ministry of Interior in Bialystok, Poland, between 1st September, 2014 and 30th April, 2015 taking part in the prospective cross-sectional study devoted to different aspects of frailty syndrome in geriatric in-patients. The study population included patients with the Active Standing Test (AST) result documented in the medical record. AST is performed in the department usually in the morning on the second day of patient’s hospital stay as a part of comprehensive geriatric assessment (CGA). After a resting period of 10 minutes, blood pressure is measured electronically (Automatic Philips IntelliVue MP5 Monitor) on the non-dominant arm with the patient lying down. The patient is then asked to stand up, and the blood pressure is measured again during the first and the third minute after standing . In the The following variables characterizing the patients were retrieved from medical charts: age, gender, blood pressure (BP) and pulse pressure (PP) records at admission, prevalence of diseases that can increase the risk of orthostatic hypotension, number of chronic diseases , number of medications taken at admission, and taking medicines that affect blood pressure and increase the risk of OH . Physical and mental abilities of an older person were assessed, based on the results of tests and scales routinely carried out within comprehensive geriatric assessment performed in the geriatric ward . Chronic kidney disease (CKD) i.e. stage 3, 4 and 5 CKD according to Kidney Disease Outcome Quality Initiative (KDOQI) was diagnosed if GFR was <60ml/min/1.73m2. The high risk of falls was diagnosed if POMA score was<19, and if TUG time was ≥14s. Malnutrition was suspected if albumin level was <35g/L, or if MNA-SF score was below 8. Sarcopenia was diagnosed if MAC was ≤22cm or CC was <31cm. Slowness and weakness were diagnosed according to criteria proposed in the literature- cut off points were stratified by gender and height in case of slowness and by gender and BMI quartiles in case of weakness . The diaThe study was approved by the Ethics Committee at Medical University in Bialystok (R-I-002/305/2013). All procedures performed in the study were in accordance with the ethical standards of the Medical University in Bialystok research committee and with the Helsinki declaration and its later amendments. Personal data were not identifiable during the analysis. The study can be classified as a study of ‘usual practice’. Data are available to researchers and applications should be made direct to the corresponding author.2 tests, while the independent samples t-test and Mann-Whitney U test were used to compare measures of central tendency (means and medians). It was followed by a multivariable logistic regression including all predictors with a P value less than 0.1. Missing values were omitted and statistics in such cases were calculated for the adequately reduced groups. A P value of less than 0.05 was regarded as significant.Data were collected and analyzed using IBM SPSS Version 18 Software suit , and presented as means and standard deviation for normally distributed and as medians and interquartile range for not normally distributed continuous variables, and the number of cases and percentage for categorical variables. Shapiro Wilk test was used to assess the distribution of variables. Proportions were compared using χThere were 416 patients hospitalized in the study period and 353 (84.9%) had AST result documented in the medical record and were included in the study group. The median age of patients was 82 (77–86) and the majority of them was above 75 years of age (84.4%), and female (77.9%). OH was diagnosed in 57 (16.2%) patients, significantly more frequently in men. In 55 of patients with OH we managed to determine the type of hypotension. In the majority of cases  it was systolic-diastolic hypotension, less often it was systolic OH , and the least found was diastolic hypotension . In 61.8% of cases the orthostatic drop of blood pressure was noted only in the first minute of AST, in 32.7% in both measurements, and in 5.5% in the third minute of the test. In a large percentage of OH cases (44.4%), the assessment of orthostatic hypotension was possible in a sitting position only, as the patient was not able to keep a standing position.To assess the homogeneity of the groups and evaluate the possible determinants of OH, we compared patients with OH (“OH+” group) and without OH (“OH−” group) according to AST . Percentage of patients with Parkinson disease was significantly higher in the OH+ group. Patients in OH+ group were also significantly more frequently taking α1-blockers, neuroleptics  and memantine.Variables meeting the criterion p <0.1 were assumed to be included in the regression analysis. Among these variables mail gender and use alfa1-blockers were strongly correlated with each other- alfa1-blockers were not reported at all in women. Therefore, although this variable was not connected with the significant multicollinearity effect, we decided to check two models of determinants of OH− the model including variable “gender” and not including it one.A direct logistic regression analysis was performed on OH as outcome and 10 attitudinal predictors: gender (men), systolic and diastolic blood pressure values, risk of malnutrition , BMI>30 kg/m2, calf circumference (CC), Parkinson disease, taking neuroleptics, memantine, and α1-blockers. An independent positive effect associated with the prevalence of OH in AST was observed among male patients, with lower values of diastolic blood pressure, at risk of malnutrition according to MNA-SF, and taking memantine. In the model without variable “gender” Parkinson disease and taking alfa1-blockers revealed to be significant independent predictors of OH apart from previously mentioned ones.Because the AST- albeit an obligatory part of a comprehensive geriatric assessment procedure in the department- was not reported in medical records of quite a large 15.1%) percentage of patients, we looked at the differences between patients with AST and without this test results. The groups did not differ in age, gender and in a number of characteristics, taken into account in previous analyzes, but they differed in terms of degree of disability in ADL and I-ADL. Significantly more frequently AST was not made in more frail people, with higher scores of Clinical Frailty Scale and classified as severely frail  percentage of patients, mainly severely frail and dependent in ADL, and in quite a high percentage of patients the orthostatic hypotension was diagnosed in a sitting position as they were not able to keep standing. It may indicate that due to limitations in the performance of AST, the problem of OH may be underestimated in very frail and disabled patients’ population. Also a number of other factors may affect the underestimation of the incidence of orthostatic hypotension in geriatric patients in daily clinical practice. In older people it is recommended to evaluate towards the occurrence of OH regardless the presence of postural symptoms. A retrospective analysis of outpatients consequently afferent to a tertiary hospital in Milan for memory complaints, functional evaluations or comprehensive geriatric assessments during the years 2011–2014 revealed that only in 3% of them OH was found, although a high percentage of them had symptoms suggestive for OH . ConsideOH prevalence may also differ depending on the population studied as well as method and criteria of OH assessment used- AST or, for example, beat-to-beat technology , 36. TheStudies have not always shown a relationship between OH and age. Although OH was observed more frequently with age in some studies , 40, in Data from studies regarding correlation between OH and gender are contradictory. In some studies gender was not connected with the prevalence of OH , but in According to some authors OH may be treated as a marker of clinical frailty  but we dContrary to other studies’ results we did not observe any specific associations between orthostatic hypotension and multimorbidity, polypharmacy, prevalence of cardiovascular diseases, or different classes of cardiovascular medications use. But the median values of systolic and diastolic conventional blood pressure measured at admission were significantly lower in OH+ group in our study, and lower diastolic blood pressure was one of the main independent predictors of OH in logistic regression. Low blood pressure on admission to the ward may have resulted, at least in some of these patients, from an inadequate hydration status- a frequent problem in geriatrics. But it could also be a result of too intensive antihypertensive therapy. Until the results of HYVET Study it was considered both appropriate and necessary to treat elderly hypertensive patients aggressively to the same target blood pressures identified for younger patients because a number of clinical trials demonstrated that treatment of hypertension significantly reduces the cardiovascular event rate in older patients . But in Parkinson’s disease was one of the main independent predictors of OH in our study. It corresponds with the results of other studies . This coDementia was proved to be independently associated with OH in the older adult population in some studies , and OH We did not observe any correlation between OH and variables describing risk of falling  or history of falls in the last 12 months. It may be connected with the retrospective study scheme and no assessment of the occurrence of OH available in the most frail patients. The recent individual patient data (IPD) meta-analysis of prospective observational studies showed a clear and significant relationship between OH and time to the first fall incident . By prevThe results of our study have to be interpreted with caution, as the study has got some limitations, which should be mentioned. First of all, it was performed not in the sample randomly selected from the general population of older people, so the results can be generalized for the patients of the similar settings only. As it was a partially retrospective study so some limitations can result from its retrospective design . However, we were striving to meet the requirements of a prospective observation .OH affects a significant percentage of patients in the geriatric ward, although this problem may be underestimated due to limitations in the performance of AST in very frail patients. Diastolic hypotension on admission to the ward, malnutrition risk according to MNA-SF, Parkinson’s disease and some drugs used , and no frailty status per se, were significant predictors of OH.Conflict of interest: The authors declare that there is no conflict of interest regarding the publication of this article.


Kidney transplantation (KT) is the most effective way to decrease the high morbidity and mortality of patients with end-stage renal disease. However, KT does not completely reverse the damage done by years of decreased kidney function and dialysis. Furthermore, new offending agents  added in the post-transplant period increase the risk of complications. Cardiovascular (CV) disease, the leading cause of death in KT recipients, warrants pre-transplant screening based on risk factors. Nevertheless, the screening methods currently used have many shortcomings and a perfect screening modality does not exist. Risk factor modification in the pre- and post-transplant periods is of paramount importance to decrease the rate of CV complications post-transplant, either by lifestyle modification  or by pharmacological means . Post-transplantation diabetes mellitus (PTDM) is a major contributor to mortality in this patient population. Although tacrolimus is a major contributor to PTDM development, changes in immunosuppression are limited by the higher risk of rejection with other agents. Immunosuppression has also been implicated in higher risk of malignancy; therefore, proper cancer screening is needed. Cancer immunotherapy is drastically changing the way certain types of cancer are treated in the general population; however, its use post-transplant is limited by the risk of allograft rejection. As expected, higher risk of infections is also encountered in transplant recipients. When caring for KT recipients, special attention is needed in screening methods, preventive measures, and treatment of infection with BK virus and cytomegalovirus. Hepatitis C virus infection is common in transplant candidates and in the deceased donor pool; however, newly developed direct-acting antivirals have been proven safe and effective in the pre- and post-transplant periods. The most important and recent developments on complications following KT are reviewed in this article. Kidney transplant is the best treatment of ESRD and decreases the mortality rate to 29 per 1,000 patient-years1. Despite this, kidney transplant recipients still experience a high incidence of complications in the post-transplant period. On one hand, the pre-transplant period, in which the patients had a very low glomerular filtration rate (GFR) and were on renal replacement therapy, inherently confers a high risk of complications which are not completely reversed by a kidney transplant. On the other hand, new factors are added in the post-transplant period, most notably immunosuppressive medications and their side effects. Therefore, the post-transplant period is associated with a wide range of complications, including cardiovascular (CV), metabolic, oncologic, infectious, immunological, surgical, osseous, and hematologic complications. This review will focus on CV, metabolic, oncologic, and infectious complications with an emphasis on areas with important developments in recent years. We chose to review these particular complications because of their frequency and associated mortality in kidney transplant recipients  is one of the leading causes of premature mortality, and the death rate for patients on dialysis is 166 per 1,000 patient-yearsipients . Much of3. By the time patients reach ESRD, the prevalence of coronary artery stenosis ranges from 37% to 58% in asymptomatic patients4.Chronic kidney disease (CKD) is an independent risk factor for atherosclerotic coronary artery disease (CAD), and CAD incidence and severity increase as the GFR declines5. The cumulative incidence of myocardial infarction in the post-transplant period is 4.2% to 11.1% at 3 years7. Therefore, two strategies are commonly used to decrease the incidence of CV disease in post-transplant patients: (1) pre-transplant screening with subsequent treatment and exclusion of very high-risk patients from listing and (2) risk factor modifications in the pre- and post-transplant period.Although kidney transplant is the most effective way to decrease the risk of CV events, CV death still accounts for 30% of overall mortality, the most common cause of death in the post-transplant period5. Many of these risk factors persist in the post-transplant period but others can developde novo, including post-transplantation diabetes mellitus (PTDM) (previously known as new-onset diabetes after transplantation), drug-induced hypertension, drug-induced dyslipidemia, proteinuria, and chronic inflammation9. Non-traditional CV risk factors in the post-transplant period include intrarenal resistive index (RI) greater than 0.80, which is associated with higher risk of death10. Interestingly, the RI during protocol biopsies correlates more with recipients’ factors  than with graft or histologic factors10. Hypotension in the pre-transplant period might also be a risk factor for adverse outcomes in the post-transplant period, evidenced by recent studies associating the use of midodrine in the pre-transplant period with graft failure, death, and major adverse cardiovascular events (MACE) post-transplant12.The most important CV risk factors in the ESRD population include diabetes mellitus (DM), prior CV disease , dialysis vintage of more than 1 year, left ventricular hypertrophy, age greater than 60 years, smoking, hypertension, and dyslipidemia13 based on the ALERT  trial, which showed that fluvastatin decreases the risk of MACE in kidney transplant patients15. Treatment with renin–angiotensin–aldosterone system blockade to decrease proteinuria and hence to decrease CV risk has not proven to be as effective as in the general population22, but larger prospective studies are needed before reaching a definitive conclusion.Identification and optimization of modifiable risk factors are of utmost importance for prevention of CV events post-transplant. Lifestyle modifications, including exercise, smoking cessation, and maintenance of a healthy weight, are always recommended. Treatment of all post-transplant patients with a statin is suggested by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines on lipid management (grade 2A)26. However, clinicians need to be aware that the pre-transplant CV evaluation should not be the same as for any other non-cardiac surgery, particularly because of the high risk of severe allograft dysfunction (in 6% to 33% of patients) and allograft loss (in 3% to 12% of patients) if cardiac surgery is required in the post-transplant period30. Therefore, it is very important to note that the goal of the screening strategy is to decrease the CV events and mortality not only in the perioperative period but also in the long term5.The ideal screening strategy is unknown and differs across transplant centers. Current clinical guidelines are based mostly on expert opinion with a low level of evidence, but the general recommendation is the use of a risk-stratified approach in which non-invasive techniques are used first, and coronary angiography is reserved for high-risk patients or when the non-invasive tests are abnormal4. This strategy is more controversial for intermediate- and high-risk patients for several reasons. First, the accuracy of stress tests compared with that of coronary angiography is limited  and MACE . However, coronary angiography was not superior to non-invasive testing at predicting future adverse CV events. Nevertheless, the predictive ability of coronary angiography might have been falsely reduced by revascularization, which significantly decreases MACE  and all-cause mortality 32. These results might have also been affected by referral bias given that many of the patients who underwent coronary angiography had an abnormal non-invasive test previously. When revascularization is indicated, this should occur prior to transplantation5. However, clinicians need to take into account the need for antiplatelet or anticoagulation treatment after revascularization, which could delay or postpone transplantation.The same meta-analysis36 given that high calcium scores may reflect medial instead of intimal vascular calcifications  and coronary computed tomography (CT), are now being studied in the ESRD population. The correlation between CACS and angiographic CAD in the CKD/ESRD population is uncertaincations . Neverth39, and an abnormal coronary CT is an independent risk factor for adverse CV outcomes in kidney transplant candidates40. These results are from relatively small studies and require validation in larger trials with a more diverse population before the widespread use of coronary CT can be recommended as a CV disease screening method in renal transplant candidates. Furthermore, there is a safety concern of performing coronary CT in patients with residual kidney function given the exposure to iodinated contrast media. Notably, coronary CT is solely a diagnostic modality and in the event of a positive test an invasive coronary angiography and angioplasty would be needed, requiring a second exposure to iodinated contrast media. Another concern regarding most tests used for CV disease screening is the required radiation exposure in patients who will subsequently be at higher risk of cancer as a result of post-transplant immunosuppression.Coronary CT has good correlation with angiographic coronary disease41). Immunosuppression has evolved to rely more on calcineurin inhibitors (CNIs) than on corticosteroids. Despite this, the incidence of PTDM did not decline as expected, leading to the discovery of the diabetogenicity of CNIs, particularly tacrolimus42. However, since the early 2000s, the incidence of PTDM has declined16, probably due to decreased rates of rejection episodes and reduced exposure to corticosteroids and CNIs42. The 5-year incidence of PTDM according to the 2016 Scientific Registry of Transplant Recipients (SRTR) report is about 12%16.Previously, transplant immunosuppressive regimens depended on high doses of corticosteroids, which led to an increased risk of DM after transplant , and cytomegalovirus (CMV) infection52, but high body mass index (BMI) is associated with a higher risk of PTDM and worse patient and allograft outcomes55. Hence, many transplant centers exclude patients with high BMI from listing (BMI cutoff varies from 35 to 45 kg/m2 between transplant centers56). Furthermore, a significant proportion of patients gain weight in the post-transplant period, likely because of the high doses of steroids and the liberalized diet58. Case series and small studies have reported promising results of bariatric surgery pre- and post-transplant65. Attention to the possibility of malabsorption induced by bariatric surgery  is important because of an increased risk of urolithiasis, oxalate deposition in the kidney, and the potential  decreased absorption of immunosuppressive medications67.Obese patients obtain a clear benefit from kidney transplant compared with staying on dialysis46. Although tacrolimus has a higher risk of PTDM compared with cyclosporine A68, the former is generally preferred because of the lower risk of rejection and higher graft survival69. The benefit of early corticosteroid withdrawal has been controversial; the largest randomized trial found no difference in PTDM development at 5 years post-transplant with corticosteroid maintenance versus early withdrawal70. This contrasts with the findings of an earlier meta-analysis that showed a reduced risk of PTDM with early steroid withdrawal but also an increased risk of allograft rejection71. When steroid withdrawal is chosen, the PTDM incidence is similar if steroids are given for 10 days versus an intraoperative bolus only, but the incidence of rejection is higher in the second group72. Another potential strategy to decrease the risk of PTDM would be to use CNI-free regimens. Use of belatacept, a T-cell co-stimulation blocker, reduces the risk of PTDM by 39% compared with CNIs73. Although mammalian target of rapamycin (mTOR) inhibitors are associated with a better glycemic profile than tacrolimus, they result in a worse lipid profile and higher rejection risk42.Changes in immunosuppression should be based on overall patient and allograft benefit rather than on the risk of PTDM development alone42. In the early post-transplant period, it is recommended to treat hyperglycemia with insulin since it is the safest and most effective agent in the context of high corticosteroid doses46. Furthermore, this approach appears to reduce the odds of developing PTDM by 73% in the first year post-transplant74. After corticosteroid doses are reduced, treatment with oral anti-hyperglycemic agents is recommended, but the choice of specific agent should be individualized. Because of a lack of evidence, the most recent consensus recommendations were unable to propose a hierarchy of anti-hyperglycemic agents for PTDM46. The most commonly used anti-hyperglycemic medications post-transplant include metformin, sulfonylureas , and meglitinides . Newer medications such as DPP-4 inhibitors  and GLP-1 agonists (exenatide and liraglutide) have been proposed for PTDM given their ability to counteract the effects of CNIs and corticosteroids by increasing glucose-dependent insulin secretion and inhibiting glucagon secretion75. In the general population, treatment with GLP-1 agonists decreases MACE77 but this has not yet been confirmed in the kidney transplant population. Although no long-term randomized trials of these agents using clinical end points have been carried out for PTDM, studies have demonstrated that they are safe and effective in controlling hyperglycemia in post-transplant patients84. Finally, SGLT-2 inhibitors  have been shown to be effective in the general population in controlling hyperglycemia, reducing proteinuria, slowing kidney function decline, promoting weight loss, decreasing blood pressure, and reducing CV risk87. To date, only case reports and case series have reported the use of SGLT-2 inhibitors in the post-transplant period, and the biggest series of 25 patients has only been reported in abstract form90. These small series have shown that the effect of SGLT-2 inhibitors post-transplant is similar to the general population in terms of glucose control, weight loss, and decrease in blood pressure90. However, no long-term data are available, and no benefits in hard outcomes such as death, MACE, or graft failure rate have been demonstrated in kidney transplant recipients. Furthermore, some features of these medications, including the increased risk of genitourinary infections, volume depletion, ketoacidosis, and amputations, are particularly concerning for kidney transplant recipients92. Given the retrospective nature of the studies carried out to date in the post-transplant period with SGLT-2 inhibitors and the small number of patients included, we cannot reach a definitive conclusion on their safety profile90. A prospective interventional trial is ongoing (EMPTRA-DM) and we anxiously await the results93.Treatment of DM in the post-transplant period includes lifestyle modification with particular attention to healthy weight maintenance as well as pharmacologic therapy. Owing to the lack of evidence derived from well-designed prospective clinical trials investigating differences in hard clinical end points such as mortality, allograft loss, and CV events in this population, the optimal pharmacologic agent in transplant recipients is not well established19. The standardized incidence ratios (SIRs) for infection-related malignancies—that is, Epstein–Barr virus (EBV)-associated lymphoma, Kaposi sarcoma (KS), hepatocellular carcinoma, genital and gastric cancers—are significantly elevated in kidney transplant recipients94. However, dozens of other cancer types unrelated to infection are also more common in the transplant population; the highest SIR is for the following cancers: squamous cell cancers of the skin and lip, renal cell carcinoma (RCC), cholangiocarcinoma, and salivary gland cancer19. Moreover, the incidence of lung and colorectal cancers, which are very common in the general population, is even higher in the transplant population94. In contrast, the SIR of prostate and breast cancer is not higher in transplant recipients compared with the general population94 112, recent large studies have failed to show a difference in overall malignancy risk between patients on mTOR inhibitor–based immunosuppression and other regimens116. Some studies have not included non-melanoma skin cancer in their analysis, but most of the studies that did have found a decreased risk of non-melanoma skin cancer 119. Nonetheless, mTOR inhibitor–based immunosuppression regimens have been associated with increased risk of mortality115 and post-transplant lymphoproliferative disorder121. Therefore, it is not recommended to change to mTOR inhibitor–based regimens after a cancer diagnosis. The only situation in which conversion to mTOR inhibitor–based regimen is recommended is in transplant patients diagnosed with KS122 because of reports of complete regression of the KS lesion after conversion125.mTOR inhibitors  suppress growth and proliferation in malignant cells127. However, case reports and series have reported a high risk of allograft rejection and loss with monoclonal antibodies against PD-1 but the incidence of this outcome is unknown129. Conversely, this outcome is seen less frequently with agents targeting CTLA-4127. A recent review found 17 reported solid organ transplant recipients  treated with these agents. One (16%) of six patients treated with the CTLA-4 inhibitor ipilimumab had allograft rejection, compared with 5 (62%) of 8 patients treated with PD-1 inhibitors, and 2 (66%) of 3 patients treated with CTLA-4 followed by PD-1 inhibitors130. A similar pattern was seen in the subset of kidney transplant recipients alone130. Further research is necessary to clarify the safety and effectiveness of checkpoint inhibitors in transplant recipients and for development of regimens that minimize the risk of allograft rejection, such as combining these agents with mTOR, BRAF, mitogen-activated protein kinase (MEK), and Bruton’s tyrosine kinase (BTK) inhibitors130.Cancer immunotherapy is an emerging field requiring particular attention in kidney transplant recipients. Checkpoint inhibitors, which target the programmed cell death pathway (PD-1 and PD-L1) and the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), are effective in the treatment of several types of cancers, including melanoma, RCC, and non-small cell lung cancer17. The degree of immunosuppression and epidemiological exposures are the main determinants of the risk of infections. Transplant infectious disease experts typically divide the post-transplant period into three roughly different intervals131:Infectious complications are common during the post-transplant period and account for 13% of overall mortality in kidney transplant recipients(1)first month post-transplant, when infections are either a complication of the surgery/hospitalization or pre-existing in the donor or recipient;(2)Pneumocystis jirovecii pneumonia, CMV or other herpes virus infections, mycobacterial infections, and so on) often happen, warranting prophylactic measures to prevent such infections;one to six months post-transplant; this is the period when immunosuppression is often the highest and opportunistic infections ((3)after 6 to 12 months post-transplant, when immunosuppression is usually more stable and lower than in previous periods.This timeline is obviously altered by heightened immunosuppression due to rejection episodes. During all of these periods, kidney transplant recipients are also at higher risk of “garden-variety” infections such as community-acquired pneumonia, urinary tract infections, and so on.In this article, we decided to focus on three particularly important subjects that either have changed dramatically in the last few years  or warrant special attention in kidney transplant recipients , despite not being the most common infectious complications during the post-transplant period.134. The prevalence of HCV in the ESRD population is significantly higher than in the general population, a finding which continues after transplantation135. HCV infection is associated with worse allograft outcomes , hepatic complications , PTDM, CV disease,de novo or recurrent glomerulonephritis, and overall worse patient survival141. Nevertheless, HCV-infected patients who receive a transplant have significantly lower morbidity and mortality than HCV-infected patients who remain on the waiting list144.HCV infection is associated with higher incidences of CKD, faster progression to ESRD, and higher morbidity and mortality145, and ribavirin causes hemolytic anemia in patients with low GFR146. The recent development of direct-acting antivirals (DAAs) has dramatically changed HCV treatment, making interferon and ribavirin treatment essentially obsolete. Several all-oral, interferon-free DAA regimens are highly effective and safe in CKD stages 4–5, ESRD, and kidney transplant populations with sustained virological response (SVR) rates of 90% to 100%163. DAA treatment in kidney transplant recipients results in SVR rates ranging from 98% to 100%163. However, 36% of transplant patients require CNI dose adjustment, but no increased risk of acute rejection has been reported163. Screening for hepatitis B virus (HBV) infection is recommended before starting HCV treatment given the risk for HBV reactivation with DAAs164.Historically, treatment of HCV infection included interferon or pegylated interferon with or without ribavirin. Owing to a high rate of allograft rejection and loss, interferon is not recommended in transplant recipients167. This leads to two important questions: (1) Should HCV-positive candidates be treated with DAAs before or after kidney transplantation? (2) Is it safe to transplant HCV-positive organs into HCV-negative recipients?The availability of HCV-positive deceased donor kidneys has increased dramatically as a result of the opioid epidemic in the USA. Moreover, the waiting time for an HCV-positive kidney is much lower than for an HCV-negative kidney as these organs are currently not offered to HCV-negative transplant candidates135.In terms of timing of HCV infection treatment, the most important factors to consider are DAA accessibility, the availability of HCV-positive organs, and the waiting time reduction in the area where the patient would be transplanted. If using HCV-infected donor kidneys results in a significant reduction in waiting time and DAAs are available, most patients would benefit from transplantation first followed by HCV treatment after transplantation. However, situations exist where treatment of HCV infection is indicated before transplant, including severe extrahepatic HCV manifestations such as mixed cryoglobulinemia syndrome, compensated cirrhosis with high risk of liver disease progression, and a living donor available only after 24 weeks (where there is no benefit of delaying the 12-week treatment and 12-week post-treatment monitoring for SVR)168, 20 HCV-negative patients have been transplanted with HCV-infected kidneys followed by initiation of elbasvir/grazoprevir on post-transplant day 3. All recipients developed a positive HCV viral load post-transplant, but within 4 weeks of treatment the virus was undetectable, and 100% of patients achieved SVR at 12 weeks168. At 1 year of follow-up, allograft function, blood pressure, and proteinuria were excellent155. Another 10 HCV-negative recipients have been transplanted with HCV-positive kidneys in the EXPANDER-1  trial in which elbasvir/grazoprevir was started immediately before transplantation. Only three patients had detectable HCV RNA early post-transplant, and 100% had negative HCV viral load at 12 weeks170. Both trials showed a good safety profile of elbasvir/grazoprevir early post-transplant and good early allograft outcomes170. Currently, this practice is recommended in the controlled setting of clinical trials only, but if the results of the THINKER and EXPANDER-1 trials are confirmed in larger studies, it might become a widespread practice that would expand the donor pool.Two trials evaluating the safety of transplanting HCV-positive organs to HCV-negative recipients have been published recently. In the THINKER (Transplanting Hepatitis C kidneys Into Negative Kidney Recipients) trial171.CMV remains a frequent infectious complication after kidney transplantation. Active CMV infection can lead to a viral syndrome (CMV syndrome) or tissue-invasive disease—including colitis, pneumonitis, nephritis, hepatitis, encephalitis, and retinitis—or both. Furthermore, CMV infection has “indirect effects”, including increased risk of allograft failure172. Another risk factor is level and type of immunosuppression; incidence is higher in patients induced with lymphocyte-depleting agents , and incidence is lower with mTOR inhibitor–based chronic immunosuppression regimens179.The most important risk factor is CMV serostatus in the donor and recipient, and the highest risk is in the CMV IgG-negative recipient transplanted with a CMV IgG-positive organ172. Pre-emptive therapy involves CMV viral load monitoring at regular intervals (most often weekly), and therapy is started only when a specific viral load threshold is crossed. Because of the variability of the tests, no universal threshold to initiate therapy has been defined181. This approach eliminates the possibility of drug side effects and prevents late CMV infection better, but early CMV infection is more frequent. Moreover, this approach may be more difficult to implement and the costs of frequent monitoring might also be high172. A randomized trial comparing both approaches found no difference in the incidence of CMV disease182. The role of screening for CMV viremia later after transplantation is not well established.CMV prevention strategies are commonly used post-transplant. The main approaches are universal prophylaxis or pre-emptive therapy. Universal prophylaxis entails administration of antiviral drugs  to all patients or those at higher risk of CMV infection starting the first 10 days post-transplant and continuing for 3 to 6 months. Treatment duration is guided by the specific CMV status of donor and recipient. This approach is easier to implement and prevents early CMV infection; however, late CMV infection is more common with this approach, drug costs may be high, and patients often experience drug-induced adverse events, including leukopenia and hepatitis, among others183, 321 solid organ transplant patients (>70% kidney transplant recipients) with CMV viremia, CMV syndrome, or CMV disease were randomly assigned to ganciclovir or valganciclovir. Viremia eradication and treatment success were similar in the two groups. Nevertheless, international consensus guidelines still recommend intravenous ganciclovir as the initial treatment for patients with life-threatening CMV infection172. Reduction of the intensity of immunosuppression is also associated with higher CMV eradication rates184.Treatment of CMV syndrome or tissue-invasive disease consists of oral valganciclovir or intravenous ganciclovir. In the Study of Valcyte Compared to Ganciclovir in Patients with Cytomegalovirus Disease who are Solid Organ Transplant Recipients 172. Genotypic assays to detect mutations are used to test for resistance. In 90% of patients, mutation of the UL97 kinase gene appears first with varying degrees of resistance to ganciclovir but does not confer cidofovir or foscarnet resistance. UL54 mutations evolve later, conferring increased ganciclovir resistance and possibly cidofovir or foscarnet resistance or both. Depending on the mutation encountered, treatment with high doses of ganciclovir, foscarnet, or cidofovir could be indicated, but no controlled trials have defined the best intervention in these cases172.Drug resistance needs to be suspected when there is persistent CMV viremia or disease despite prolonged antiviral therapy (6 or more weeks of cumulative drug exposure or more than 2 weeks of ongoing full-dose therapy)188. The most important risk factor for BK virus nephropathy development is the level of immunosuppression, but recent studies have demonstrated the importance of BK virus–specific T-cell functionality190 and BK virus seroprevalence in donors and recipients, and risk is higher in those donor-positive/recipient-negative pairs192. Antibody-depleting induction therapy increases the risk of BK virus nephropathy, whereas mTOR inhibitor reduces the risk193.BK virus is a polyomavirus that is highly seroprevalent in humans but causes disease only in immunocompromised patients. Following kidney transplantation, BK virus causes tubulointerstitial nephritis in 1% to 10% of patients198. The KDIGO guidelines on kidney transplant recipients recommend urine or blood PCR monthly for the first 3 to 6 months post-transplant and then every 3 months until the end of the first post-transplant year122. However, other international consensus guidelines suggest continuing screening every 3 months until the end of the second year post-transplant and yearly thereafter199. Definitive diagnosis is made with histology on kidney allograft biopsy showing tubulointerstitial nephritis with cytopathic changes and positive immunohistochemistry for SV40131.Screening of BK virus nephritis relies on testing for viral replication in urine and blood. Viral replication in urine is tested with urine cytology looking for decoy cells or by polymerase chain reaction (PCR), whereas plasma or whole blood viral replication is confirmed by PCR. In general, the correlation with BK virus–associated nephropathy is higher for viremia (positive BK PCR in blood), lower for viruria (positive BK PCR in urine), and lowest for urine cytology 185,194121. However, the specific strategy of immunosuppression reduction is not well stablished and is mainly center-specific. A common practice is withdrawal of the antimetabolite drug  and decrease of CNI dosing by 50%. Alternative approaches have been to stop tacrolimus and initiate either cyclosporine or an mTOR inhibitor. However, the evidence to support any of these approaches is low204. Some agents with antiviral properties have been suggested. Adding cidofovir or leflunomide does not increase graft survival205. Treatment with intravenous immunoglobulin (IVIG) is promising based on the fact that many formulations of IVIG have neutralizing BK antibodies206 and several case series have described its efficacy208, but large randomized controlled trials are needed before its widespread use can be recommended. Although quinolones have been reported to have anti-BK properties, randomized trials have shown no benefit of adding levofloxacin210.The cornerstone of therapy is reduction of immunosuppressionKidney transplant recipients have a high risk of complications due to adverse events of potent immunosuppressive medications and their pre- and post-transplant complex medical history. It is important for the clinician taking care of these patients to be aware of the most common complications encountered in the post-transplant period and how to screen, diagnose, and treat them. A multidisciplinary team approach is often required given the multiple complications that fall into different medical and surgical specialties in kidney transplant recipients.


Professional athlete training is significantly different from recreational physical activity, and sustained, repetitive exposure to over-strenuous and intensive training may result in critical changes of most systems and organs in a sportsman's body.  The assessment of the influence of multiannual strength-endurance training on the autonomic nervous system (ANS) and cardiovascular system (CVS) among the rowers of Polish national team.  20 rowers, aged 20–30, seniors of Polish national team were qualified into the study. The functional examination of ANS was conducted by means of Task Force® Monitor system. The assessed parameters included hemodynamic parameters, heart rate, and blood pressure variability and reflexes sensitivity of baroreceptors. In order to examine and compare the reaction of autonomic nervous system the subjects underwent a tilt test. p = 0.0030), SI , CI , and significantly lower levels of HR  and TPRI  compared to the control group, were found. After the tilt test the levels of HR (p = 0.0005) and TPRI (p = 0.0128) were significantly higher but SI (p > 0.001) and CI (p = 0.0006) were significantly lower in the study group compared to the control.  In the study group, significantly higher levels of sBP (129.3  ±  12.2 vs 118.3 ± 8.4,  Multiannual strength-endurance training connected with rowing activities substantially modulates the activity of cardiovascular and autonomic nervous system, influences the volumetric workload of the heart and structural changes, and increases the sensitivity of reflexes of arterial baroreceptors. Active lifestyle and regular endurance (oxygen) trainings have a positive influence on the cardiac muscle and other components of the cardiovascular system . HoweverThe research was conducted on 20 rowers of Polish senior national team at a rest period after a starting season. The criteria for inclusion in the research included: sex, professional rowing practice (at least 10 years), good general health condition, and lack of any cardiovascular and autonomic nervous systems diseases. In order to maintain homogeneity, the clinical reference group included 20 men aged 25–35. All men were professionally active and were characterised by general good health condition, lack of ANS diseases, and healthy cardiovascular system. The characteristics of the basic biological traits of the subjects are shown in 2max among rowers was 6.17 l/min with the average threshold value (4 mmol) which equals 378.75 W. The maximum average acidification ability was 14.10 mmol/l with the maximum ultimate power 496 W.The examination was conducted in a training microcycle in a resting phase. The period lasted 4–6 weeks and was characterised by gradual decrease in starting performance—after the end of the starting season. During that period, the trainings were dominated by general physical exercises: running, gym exercises, gymnastics, team sports, or swimming. In order to measure the physical endurance, the rowers underwent the test of gradually growing strength on Concept II rowing machine. The test included eight three-minute stages, separated by thirty-second breaks. The load in the test started from 170 W and was increased with each stage by 50 W at the rowing pace starting from 14 strokes/minute and increased by 2 strokes/minute in each stage. During the thirty-second breaks a blood sample was taken from an earlobe with Super GL 2 device  in order to mark the lactate concentration. The heart beat frequency (HR) was persistently monitored with a Sport Tester (Polar) and indicators of gas exchange were tested with a mobile MetaMax 3B device . The average value of VOThe test took place in the morning, 30 minutes after a meal. In order to eliminate the impact of stress related to participation in the research, each subject was thoroughly informed and acquainted with the methodology of the research and methods applied. All examinations were conducted in the conditions complying with the criteria of functional examinations of the autonomic nervous system. The examination room was deafened and darkened, and the air conditioning system kept the temperature and humidity constant. The functional examination of the autonomic nervous system was a non-invasive procedure thanks to Task Force® Monitor system. The assessed parameters included hemodynamic parameters, cardiac contractility, work of left and right ventricles, heart rate, blood pressure variability, and sensitivity of reflexes of baroreceptors.®measuring system includes the following components: (1) a device for a continuous measurement of blood pressure (contBP), (2) two-channel electrocardiograph (ECG), (3) impedance cardiograph (ICG), and (4) a device for oscillometric measurement of blood pressure (oscBP). All the components are operated by means of the integrated computer system and all, except for the oscBP device, record biological signals in a beat-to-beat mode. The system calibrates automatically thanks to its integrated generators. Measurements which are false or exceed the biological norms are detected and automatically deleted by the TFM system [The recording of the biological signals was non-invasive thanks to Task Force® Monitor system  and subject-friendly equipment used. Task Force MonitorM system , 15.In order to assess the changes in autonomic nervous system an indirect method—spectral analysis—was used. It is based on the analysis of RR interval and the signal of blood pressure in a continuous mode i.e., heart beat by heart beat. The signals are transformed from the time domain into the frequency domain –20. The Spontaneous activity of the reflexes of arterial baroreceptors was measured using a sequence method. The method is based on establishing at least three subsequent heart beats during which there is an observed increase in systolic blood pressure and extension of RR interval—a cumulative sequence, or a decrease in systolic blood pressure and shortening of RR interval—a decreasing sequence. The thresholds are calculated with the accuracy of 1 mmHg for the systolic blood pressure and 6 ms for the RR interval , 16, 17.t-test and Mann–Whitney U test—were used depending on the distribution characteristics of the analysed variables. All the calculations were made using Statistica 9.0 software  where the p ≤ 0.05 value was considered statistically significant.Standard of continuous variables distribution was formulated with the Shapiro-Wilk test, and the statistical characteristics were shown as arithmetic means and standard deviations (±SD). In order to assess the significance of the variations between the measured values obtained in the group of rowers and in the clinical control group, two tests—Student's The rowers scored significantly higher on systolic blood pressure (sBP), stroke index (SI), cardiac index (CI) and all sequences of baroreceptors (BRS), as well as substantially lower on heart rate (HR), and total peripheral resistance index (TPRI) .It was observed that the rowers obtained higher results of index of contractility (IC), acceleration index (ACI), Heather index (HI) and left ventricular work index (LVWI) and substantially lower results of systolic time ratio (STR) than subjects in the control group .p = 0.0269) and higher on the frequency of the HRV spectrum  as well as spectral HRV power density   .p = 0.0005) and total peripheral resistance index  as well as lower results of stroke index  and cardiac index . The groups did not differ significantly in systolic blood pressure , diastolic blood pressure , and mean blood pressure levels   .Multiannual strength-endurance rowing training substantially decreases heart rate and modulates the function of autonomic nervous system. One of the main results of professional rowing training is the increase volumetric workload of the heart and structural changes related to that.2max) the compared groups differed only by morphometric characteristics of the left ventricle. The relevant differences of the left ventricle systolic activity  were revealed only during the effort equal to 60%–100% VO2max [The examined rowers had significantly higher average values of stroke volume (SV) and stroke index (SI) than men in the reference group, as well as substantially higher level of cardiac output (CO) and its derivative—cardiac index (CI). It is worth noticing that the abovementioned changes occurred despite significantly lower heart rate (HR) compared to the reference group. The only significant differences between the two groups in terms of resting parameters of blood pressure concerned systolic blood pressure (sBP), which was significantly higher in the rowers than reference group. The results show a possible increase in cardiac output and stroke volume and a significant decrease in the average value of vascular resistance and total peripheral resistance index in the group of rowers, which are probably the result of better development of muscular layer of arterial walls. The results prove that rowing-related effort is mainly of dynamic nature. Similar adaptive changes of cardiovascular system to the sustained and regular physical effort were shown in the recently published research of men aged >60 who used to be professional athletes and were physically active throughout their lives . An incr% VO2max . Also, a% VO2max –20. The Both the literature data and the results of this study show that the main functional element significant for improvement of cardiac inotropy of professional sportsmen is the activity of autonomic nervous system. As it was previously mentioned, the study showed a few relevant differences in resting parameters of heart rate variability and blood pressure variability indexes between the rowers and the control group. But for the growth of LF-RRI, the results of HRV and BPV spectral analysis indicated a minor domination of parasympathetic system in the group of rowers. The increased parasympathetic stimulation is supported by the higher number of sequences from baroreceptors and significantly higher average slope of the function curve of linear regression of all baroreceptors registered in the sequence recorded among the rowers. In present times it is a fact that regular moderate endurance effort has a healthy influence on ANS. It lowers the sympathetic activity and increases the parasympathetic activity. These changes cause a decrease in heart rate at rest and during submaximal effort –17. Recetotal-events event count). All these changes reflect adaptation to the post-tilt decrease in venous return and lower level of ventricle filling. The analysed data gathered after the tilt test showed that the compared groups obtained diversified results of the response to orthostatic stimulus. In the group of rowers, it was noticed that as a result of the tilt test there was a significant decrease in stroke volume (SV), stroke index (SI), index of contractility (IC), acceleration index (ACI), parasympathetic activity (a decrease in HR-RRI and HF-dBP), and average slope of the function curve of linear regression of all baroreceptors sequences . What is more, the group of rowers reacted by a substantially higher growth of the heart rate (HR), total peripheral resistance (TPR), total peripheral resistance index (TPRI), and systolic time ratio (STR), as well as significantly less perspicuous growth of left ventricular work index (LVWI) and the number of total baroreceptors sequences . Rowers, contrary to the control group, showed a decrease in cardiac output (CO), cardiac index (CI), and Heather index (HI). Although most of these differences between the two groups seem to be a derivative of the discrepancies observed during the examination at the start position, some of them  may also reflect a faster and more effective adaptation of sportsmen's cardiovascular systems to sudden changes of hemodynamic conditions.The tilt test showed a correct response of the rowers and the reference group to an orthostatic stimulus, as shown in the growth of systolic (sBP), diastolic (dBP) and mean (mBP) blood pressure, which is the result of the containment of intracardiac parasympathetic activity, intensification of vasoconstrictive sympathetic activity and growth of total peripheral resistance (TPR). What is more, the impact of orthostatic stimulus resulted in a significant decrease in cardiac contractility parameters: index of contractility (IC) and acceleration index (ACI) along with the growth of systolic time ratio (STR). Both groups were characterised by the decrease in parasympathetic activity as shown in the decreased HR-RRI value and growth of the total number of baroreceptors sequence (There is little literature data on the influence of orthostatic stimulus on sportsmen and people who are not physically active, and the results obtained in such studies are frequently inconsistent . In one Multiannual rowing training substantially modulates the activity of autonomic nervous system by increasing the volumetric workload of the heart and structural changes related to that, and intensifies the sensitivity of the reflexes of arterial baroreceptors, which seems to be beneficial when practising a strength-endurance sport discipline. Due to that, the observed changes, which contrast with the observation results of young healthy men, justify the necessity to monitor them in order to prevent possible pathological effects.