Function In Renal Transplant Recipients Research Articles

Metabolic Syndrome in Thai Renal Transplant Recipients: A Multicenter Study.

BACKGROUND Many renal transplant recipients develop complications such as obesity, posttransplantation diabetes mellitus, and dyslipidemia. There have been few studies of metabolic syndrome (MS) in Asian renal transplant recipients. MATERIAL AND METHODS This cross-sectional study was performed in 303 patients in 5 transplant centers in Bangkok, Thailand. The diagnosis of MS was based on the criteria of the modified NCEP-ATPIII, and chronic allograft dysfunction was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m^2. RESULTS Of 303 recipients, MS was diagnosed in 94 cases (31.0%) and the prevalence of MS in the first 3 years and after 3 years posttransplantation were 21.4% and 34.7% (P=0.042), respectively. There was an association between advanced age and chronic allograft dysfunction and higher prevalence of MS. Regarding non-anti-hypertensive and non-hypoglycemic medications, m-TOR inhibitor (odds ratio [OR], 2.14; 95% CI, 1.02-4.5) was associated with the prevalence of MS. Multivariate analysis revealed MS was associated with the use of beta-blockers (OR, 3.17; 95% CI, 1.88-5.32). Patients with no MS components had 26.9% prevalence of chronic allograft dysfunction and patients with higher numbers of MS components had 87.5% prevalence of chronic allograft dysfunction, which was significantly different (P=0.022). CONCLUSIONS Our study revealed that the prevalence of MS was higher in patients with higher numbers of MS components, especially after 3 years posttransplantation. Presence of more components of MS was associated with worse renal function in renal transplant recipients.

Autologous bone marrow derived mesenchymal stromal cell therapy in combination with everolimus to preserve renal structure and function in renal transplant recipients.

BackgroundKidney transplantation has improved survival and quality of life for patients with end-stage renal disease. Despite excellent short-term results due to better and more potent immunosuppressive drugs, long-term survival of transplanted kidneys has not improved accordingly in the last decades. Consequently there is a strong interest in immunosuppressive regimens that maintain efficacy for the prevention of rejection, whilst preserving renal structure and function. In this respect the infusion of mesenchymal stromal cells (MSCs) may be an interesting immune suppressive strategy. MSCs have immune suppressive properties and actively contribute to tissue repair. In experimental animal studies the combination of mammalian target of rapamycin (mTOR) inhibitor and MSCs was shown to attenuate allo immune responses and to promote allograft tolerance. The current study will test the hypothesis that MSC treatment, in combination with the mTOR inhibitor everolimus, facilitates tacrolimus withdrawal, reduces fibrosis and decreases the incidence of opportunistic infections compared to standard tacrolimus dose.Methods/design70 renal allograft recipients, 18–75 years old, will be included in this Phase II, open label, randomized, non-blinded, prospective, single centre clinical study. Patients in the MSC treated group will receive two doses of autologous bone marrow derived MSCs IV (target 1,5x106, Range 1-2x106 million MSCs per/kg body weight), 7 days apart, 6 and 7 weeks transplantation in combination with everolimus and prednisolone. At the time of the second MSC infusion tacrolimus will be reduced to 50% and completely withdrawn 1 week later. Patients in the control group will receive everolimus, prednisolone and standard dose tacrolimus. The primary end point is to compare fibrosis by quantitative Sirius Red scoring of MSC treated and untreated groups at 6 months compared to 4 weeks post-transplant. Secondary end points include: composite end point efficacy failure (Biopsy Proven Acute Rejection, graft loss or death); renal function and proteinuria; opportunistic infections; immune monitoring and “subclinical” cardiovascular disease groups by assessing echocardiography in the different treatment groups.DiscussionThis study will provide information whether MSCs in combination with everolimus can be used for tacrolimus withdrawal, and whether this strategy leads to preservation of renal structure and function in renal recipients.Trial registrationNCT02057965.

Longitudinal analysis of T and B cell phenotype and function in renal transplant recipients with or without rituximab induction therapy.

BackgroundPrevention of rejection after renal transplantation requires treatment with immunosuppressive drugs. Data on their in vivo effects on T- and B-cell phenotype and function are limited.MethodsIn a randomized double-blind placebo-controlled study to prevent renal allograft rejection, patients were treated with tacrolimus, mycophenolate mofetil (MMF), steroids, and a single dose of rituximab or placebo during transplant surgery. In a subset of patients, we analyzed the number and phenotype of peripheral T and B cells by multiparameter flow cytometry before transplantation, and at 3, 6, 12, and 24 months after transplantation.ResultsIn patients treated with tacrolimus/MMF/steroids the proportion of central memory CD4+ and CD8+ T cells was higher at 3 months post-transplant compared to pre-transplant levels. In addition, the ratio between the percentage of central memory CD4+ and CD4+ regulatory T cells was significantly higher up to 24 months post-transplant compared to pre-transplant levels. Interestingly, treatment with tacrolimus/MMF/steroids resulted in a shift toward a more memory-like B-cell phenotype post-transplant. Addition of a single dose of rituximab resulted in a long-lasting B-cell depletion. At 12 months post-transplant, the small fraction of repopulated B cells consisted of a high percentage of transitional B cells. Rituximab treatment had no effect on the T-cell phenotype and function post-transplant.ConclusionsRenal transplant recipients treated with tacrolimus/MMF/steroids show an altered memory T and B-cell compartment post-transplant. Additional B-cell depletion by rituximab leads to a relative increase of transitional and memory-like B cells, without affecting T-cell phenotype and function.Trial RegistrationClinicalTrials.gov NCT00565331

Acute Graft Pyelonephritis During the First Year After Renal Transplantation

IntroductionUrinary tract infections are the most common infections in renal transplant recipients. Acute graft pyelonephritis (AGPN) is considered a potential risk factor for poorer graft outcomes; however, its clinical impact still remains controversial. MethodsThis study analyzed urine cultures performed within the first 12 months after renal transplantation with reference to clinical data of patients who received a renal transplant at Gdańsk Transplantation Centre between January 2007 and December 2009. Renal function assessed by creatinine concentration and estimated glomerular filtration rate was recorded 24 months after renal transplantation. ResultsThis study examined urine cultures and clinical data from 209 renal transplant recipients, including 59.3% men, with a mean age of 46 ± 14 years. We observed 70 AGPN episodes defined as the presence of significant bacteriuria, fever >38°, and/or graft pain and/or acute graft function impairment, including 13 cases of bacteremia, in 46 patients. This accounted for 22% of all diagnosed urinary tract infections. Over 80% of all AGPN episodes were diagnosed beginning from the second month posttransplantation, and the most frequently isolated uropathogen was Escherichia coli (65.7%, n = 46). Female sex, vesicoureteral reflux, or strictures at the ureterovesical junction and a history of cytomegalovirus infection emerged as independent predictors of AGPN. The evolution of renal graft function measured by serum creatinine concentration and MDRG eGFR rate did not differ significantly between patients with and without AGPN. ConclusionsAGPN may be a marker of an underlying impairment of urine flow, eg, due to vesicoureteral reflux or strictures at the ureterovesical junction, whereas it does not affect graft function in renal transplant recipients.

Bioimpedance Analysis Reveals Graft Function in Renal Transplant Recipients.

Introduction: Renal transplantation (RT) is the best treatment of choice for patients with end-stage renal disease. Despite improving of renal dysfunction, patients are at risk for existing or new onset of conditions as hypertension and dyslipidemia after transplantation. In present study, we aimed to determine the hydration status by bioimpedance analysis (BIA) in RT recipients and to analyse the association of body fluid status, graft function, biochemical parameters and echocardiographic measurements. Methods: Eighty two (58 male, mean age: 38.7± 11.5 years) RT recipients being followed in our centre who were using at least one anti-hypertensive treatment were enrolled into the study. Biochemical parameters as lipid profile (total, HDL and LDL cholesterol, triglyseride), parathyroid hormone, 24 hour urinary protein loss, estimated glomerular filtration rate (eGFR); transthorasic echocardiography, bioimpedance analysis (BCM, Fresenius) as systolic blood pressure, total body weight (TBW), lean tissue index (LTI), extracellular volume (ECW), intracellular volume (ICW), lean tissue mass (LTM) and phase angle (phi50) levels and renal resistive index (RRI) were evaluated. Results: TBW and ECW were significantly correlated with RRI and systolic blood pressure (p:0.001). Patients with <70 ml/min of eGFR values were divided into five groups according to each 10 ml/min decline in eGFR. RRI, urinary protein loss, pulmonary artery pressure, frequency of over-hydration, systolic blood pressure, TBW, LTI, ECW,ICW, LTM and phi50 values were significantly higher in patients with 15-50 ml/min (p:0.000), however similar in patients with 50-70 ml/min (p:0.648). Conclusion: Hypertensive RT recipients have increased TBW, LTI, ICW, FTI, LTM and phi50 values. Graft function is positively correlated with systolic blood pressure, RRI and BIA parameters. Thus, hypertensive RT recipients should be closely follow-up with RRI and BIA for an early diagnosis of loss of graft function.

Different Methods for Imputing Missing Renal Function Data: Evidence From a Large Clinical Trial in Renal Transplant Recipients.

Purpose: Missing data are a concern in studies evaluating renal function in transplant recipients (TxR) because they may introduce bias to the conclusions drawn from the data. Last observation carried forward (LOCF) is a commonly used method to impute missing data; however, it has limitations. We retrospectively explored different imputation methods for handling missing glomerular filtration rate (GFR) data in a randomized clinical trial. Methods: GFR data (MDRD-4) were analyzed for de novo renal TxR receiving everolimus (EVR, 1.5mg/day)+reduced cyclosporine (CsA) or enteric-coated mycophenolate sodium (EC-MPS, 1.44g/day)+standard CsA in the 24-month (M), randomized, multicenter study A2309. Missing GFR data due to graft loss were assigned a value of 0. For remaining patients, missing data were imputed using: 1) multiple imputation (MI): based on patient's earlier GFR values and GFR information from similar patients in same treatment arm; 2) penalty-adjustment: imputation from approach 1 reduced by 10%-100%; and 3) control-based MI: as in approach 1 but using GFR information from control arm. All models included GFR data measured over time and covariates: patient age, BMI, donor age/type. M12 GFR data after the imputations were analyzed via ANCOVA model. Results: Across time points, GFR data were missing for 8%-16% of the patients. Applying LOCF method, mean GFR difference (95% CI) between EVR and EC-MPS at M12 was 2.1 (-1.6, 5.8). MI approach resulted in a difference of 1.7 (-2.0, 5.4). With highest penalty-adjusted imputation (‘imputed values reduced by 100%’=0) the difference was 1.2 (-2.9, 5.2). GFR difference using the control-based method was 1.7 (-2.2, 5.6). Conclusion: Missing GFR data in clinical studies is a concern and should be addressed during design and conduct of studies. Sensitivity analysis using methods based on MI are recommended to assess robustness of primary analysis. For study A2309, these retrospective sensitivity analyses confirmed numerically better renal function for EVR vs EC-MPS.Table: No Caption available.DISCLOSURES:Dong, G.: Employee, Novartis. Akacha, M.: Employee, Novartis. Ng, J.: Employee, Novartis. Escrig, C.: Employee, Novartis. Bernhardt, P.: Employee, Novartis. Witte, S.: Employee, Novartis.

Sagittal Abdominal Diameter as the Anthropometric Measure of Cardiovascular and Graft Loss Risk in Renal Transplant Recipients.

Purpose: Cardiovascular disease is the most common cause of death in renal transplant recipients. Arterial stiffness plays an important role in cardiovascular diseases and is an independent predictor for cardiovascular mortality in renal transplant recipients. Studies have demonstrated sagittal abdominal diameter (SAD) presented stronger prognostic value for all-cause and cardiovascular mortality in the general population. The aim of this study is to evaluate the association between the arterial stiffness and novel anthropometric indices in renal transplant recipients. Methods: One hundred eighty one renal transplant recipients from our renal transplant outpatient clinic were enrolled into the study. All patients were evaluated for their standard clinical (age, gender, duration of hemodialysis, post-transplant time), biochemical parameters. Anthropometric measurements (waist and hip circumference, abdominal sagittal diameter) were performed for all patients. PWv was determined from pressure tracing over carotid and femoral arteries using the SphygmoCor system. We calculated the estimated GFR (eGFR) using the MDRD4 equation. Results: Patients were divided into two group according to SAD measurements. Group 1 (n:127) was defined as the patients SAD < 24.3 cm and group 2 (n:54) was defined as the patients SAD ≥ 24.3 cm. Patients in group 2 had significantly higher triglyceride, C-reactive protein, uric acid, systolic blood pressure, PWv and body mass index measurements compared to Group 1 (p<0.05 for all). In group 2 eGFR was significantly lower than group 1 (p<0.022). SAD had positive correlation with PWv, Systolic and diastolic blood pressure, body mass index, triglyceride, fasting glucose, C-reactive protein and uric acid (p<0.05 for all). Conclusions: We showed both SAD was significantly associated with several components of metabolic syndrome, inflammation and arterial stiffness as well as graft loss. Considering the significant association of visceral fat with inflammation and cardiovascular disease, estimating visceral fat by SAD could be a useful tool to stratify cardiovascular risk as well as graft function in renal transplant recipients.

Influence of CYP3A5 Polymorphisms On Tacrolimus Pharmacokinetics and Renal Function in Renal Transplant Recipients.

Influence of CYP3A5 Polymorphisms On Tacrolimus Pharmacokinetics and Renal Function in Renal Transplant Recipients.

Nonalcoholic Fatty Liver Disease in Renal Transplant Recipients Proven by Transient Elastography

BackgroundThe increasing recognition of the importance of nonalcoholic fatty liver disease (NAFLD) and its strong association with the metabolic syndrome has stimulated interest in the putative role of NAFLD in the development and progression of cardiovascular disease. Furthermore, recent studies investigated the association of NAFLD and chronic kidney disease. We analyzed the incidence of NAFLD diagnosed by transient elastography (TE) in renal transplant recipients (RTRs). We also assessed whether TE-defined NAFLD is associated with decreased graft function in RTRs. MethodsOur study included 73 RTRs with a functioning graft for more than 1 year. Liver stiffness was used to assess liver fibrosis and the controlled attenuation parameter (CAP) was used to detect and quantify liver steatosis by using TE (Fibroscan, Echosense, Paris, France). Therefore, with CAP being implemented on TE, both steatosis and fibrosis could be evaluated simultaneously. According to this evaluation, NAFLD was defined by the presence of steatosis with CAP values ≥238 dB.m−1 regardless of presence or absence of any stage of fibrosis. ResultsAccording to the TE findings, NAFLD was present in 57.5% of RTRs. We have found that the severity of liver steatosis was positively correlated with serum creatinine levels (r = 0.664; P < .0001) and negatively correlated with estimated glomerular filtration rate (eGFR; r = −0.692; P < .0001) levels. The severity of liver fibrosis was positively correlated with the serum creatinine, serum iron, and C-reactive protein levels indicating a more severe form of NAFLD in those patients. None of the investigated liver tests showed any differences between those RTR patients who had NAFLD compared to those without NAFLD. ConclusionOur results showed that RTRs have high prevalence of TE-defined NAFLD which possibly contributes to graft dysfunction. Measuring aminotransferase levels would not be a useful tool for NAFLD detection in RTRs. Our study showed the value of TE as an effective, noninvasive screening method for the diagnosis of NAFLD in RTRs.

Karyopherins: potential biological elements involved in the delayed graft function in renal transplant recipients

BackgroundImmediately after renal transplantation, patients experience rapid and significant improvement of their clinical conditions and undergo considerable systemic and cellular modifications. However, some patients present a slow recovery of the renal function commonly defined as delayed graft function (DGF). Although clinically well characterized, the molecular mechanisms underlying this condition are not totally defined, thus, we are currently missing specific clinical markers to predict and to make early diagnosis of this event.MethodsWe investigated, using a pathway analysis approach, the transcriptomic profile of peripheral blood mononuclear cells (PBMC) from renal transplant recipients with DGF and with early graft function (EGF), before (T0) and 24 hours (T24) after transplantation.ResultsBioinformatics/statistical analysis showed that 15 pathways (8 up-regulated and 7 down-regulated) and 11 pathways (5 up-regulated and 6 down-regulated) were able to identify DGF patients at T0 and T24, respectively. Interestingly, the most up-regulated pathway at both time points was NLS-bearing substrate import into nucleus, which includes genes encoding for several subtypes of karyopherins, a group of proteins involved in nucleocytoplasmic transport. Signal transducers and activators of transcription (STAT) utilize karyopherins-alpha (KPNA) for their passage from cytoplasm into the nucleus. In vitro functional analysis demonstrated that in PBMCs of DGF patients, there was a significant KPNA-mediated nuclear translocation of the phosphorylated form of STAT3 (pSTAT3) after short-time stimulation (2 and 5 minutes) with interleukin-6.ConclusionsOur study suggests the involvement, immediately before transplantation, of karyopherin-mediated nuclear transport in the onset and development of DGF. Additionally, it reveals that karyopherins could be good candidates as potential DGF predictive clinical biomarkers and targets for pharmacological interventions in renal transplantation. However, because of the low number of patients analyzed and some methodological limitations, additional studies are needed to validate and to better address these points.

Effects of Elevated Tacrolimus Trough Levels in Association With Infectious Enteritis on Graft Function in Renal Transplant Recipients

BackgroundThe bioavailability of oral tacrolimus is influenced by enterocyte metabolism, which involves CYP3A and P-glycoprotein. Viral infection–induced intestinal inflammation damages the enterocytes and causes unfavorable elevations in blood tacrolimus levels in transplant recipients, which may lead to nephrotoxicity. MethodsFrom May 2000 to May 2011, 56 renal transplant recipients receiving tacrolimus at our hospital suffered from infectious enteritis with diarrhea. We investigated the tacrolimus trough levels before and after the onset of enteritis and evaluated the influence of elevated tacrolimus trough levels on the rate of changes in serum creatinine levels. ResultsElevated tacrolimus trough levels were observed in 52 recipients (93%) after the onset of diarrhea, and the mean value was 2.3 times higher than that before the onset of enteritis (P = .0175). Tacrolimus trough levels returned to their previous levels 2 weeks after the onset of enteritis, even in recipients with >2-fold increase, following dose adjustments. Serum creatinine levels did not significantly differ between recipients with >2-fold increase in tacrolimus trough levels and those with <2-fold increase in trough levels during a 6-month period after the onset of enteritis. ConclusionsElevations in the tacrolimus trough levels due to infectious enteritis with diarrhea can improve in ∼2 weeks by adjusting the tacrolimus dosage. Such temporary elevations in the tacrolimus trough levels may not produce serious nephrotoxicity even in recipients with remarkably elevated trough levels.

A commentary on: Does Living Donor Hyperoxia Have an Impact on Kidney Graft Function After Transplantation

Dear Editor, I read with great interest the valuable article entitled “Does living donor hyperoxia have an impact on kidney graft function after transplantation?” written by Dr. Rostami et al. (1). In this project, the authors have showed the effect of living donor oxygen therapy on function of grafted kidneys in recipients and for better comparison they’ve used a control group. Moreover, they also have assessed kidney function with some sound biomarkers such as neutrophil gelatinase-associated lipocalin, interleukin-18, and tumor necrosis factor-α that can be used for early diagnosis of kidney injury. Finally, they concluded that normobaric hyperoxia of living donors before kidney transplantation had no effect on kidney function in renal transplant recipients and suggested more studies in this field. There are only a few studies that investigated this effect in human (2-4) and I appreciate the admirable effort by authors for conducting this study; however, it seems that there are some remarks in their work that I want to point them out respectfully. First, in the method part of this paper, it has just simply said that recipient patients were divided in two groups (case and control) but the difference between these two groups is not very clear. This important point can have impacts on some of the subsequent challenging points. Matching between case and control groups is a necessary part in such studies that can have important impact on the interpreting the result of a paper. Without an appropriate matching, we cannot determine one factor as responsible for the results of the study. In this paper, gender has a significant difference between case and control groups and there is not enough information about other factors that can be important in matching process like age, reason and duration of renal failure, and duration of hemodialysis. Another important point that should be taken into account is donors’ characteristics. There is not enough information about them especially those that had given kidneys to the control group. With regard to this point, it is necessary for readers of this paper to know about differences between these two groups of donors like age, gender, etc. Additionally, according to the method part of this article, donors were exposed to oxygen for at least 2 hours for two consecutive days (before transplantation). After transplantation, the recipient patients were followed for two weeks. We know that in a cross-sectional study, we evaluate the association between the exposure factors (oxygen exposing in this study) and outcome (delayed graft function in this study) simultaneously. In addition to this follow up, there is an intervention (oxygen inhalation therapy) in their study. Again, we know there is not any intervention in an observational study like a cross-sectional. Therefore, three factors namely, randomization (it is not clear how exactly the recipients were randomized in two groups), intervention and follow up, make this study very powerful. Nevertheless, with consideration of these factors, I think the design of this project cannot be a cross-sectional type. In addition, we know these methodological mistakes can have some effects on selecting tests of the data analysis and therefor, they can influence on the results. Ultimately, except gender of participants, the results of the paper contain no information about control group and comparison of it with case group. In addition, the only finding about case group that has been mentioned concerns the age but its importance is never mentioned in the discussion part. On the other hand, there are some analytical ways used in result part of this paper such as non-parametric correlation that are not reported in the method. In the other words, non-parametric test are not mentioned in the method part of the paper at all.

C-Terminal Agrin Fragment - A New Fast Biomarker for Kidney Function in Renal Transplant Recipients

Background: The C-terminal agrin fragment (CAF) is a cleavage product of agrin, the major proteoglycan of the glomerular basement membrane. This article studies if CAF could serve as a biomarker for renal function in renal transplant recipients. Material and Methods: We measured serum CAF and creatinine concentrations and calculated estimated glomerular filtration rate (eGFR) (MDRD) in 96 healthy individuals and in 110 end-stage renal disease patients undergoing kidney transplantation before and after transplantation. Correlation between CAF and creatinine concentrations/eGFR was calculated as within-patient (cWP) and between-patient correlations (cBP). Moreover, we evaluated the association of CAF with delayed graft function (DGF). The diagnostic value of CAF for early detection of DGF compared to creatinine was evaluated by receiver operating characteristics (ROC) analysis. Results: CAF concentrations strongly correlated with creatinine (r = 0.86 (cWP), r = 0.74 (cBP)) and eGFR (MDRD) (r = 0.86 (cWP), r = 0.77 (cBP)). Pre-transplant (pre-Tx) CAF concentrations were 19-fold higher than in healthy individuals (1,115.0 (258.4-3,990.0) vs. 56.6 (20.0-109.5) p<smlcap>M</smlcap>). After transplantation, CAF decreased significantly faster than creatinine (postoperative days 1-3 (POD 1-3): 562.8 (101.6-2,113.0) p<smlcap>M</smlcap>; creatinine: pre-Tx 6.9 (3.1-15.7), POD 1-3: 6.4 (1.7-12.7) mg/dl, p < 0.001). Stable concentrations were reached 1-3 months after transplantation for CAF and creatinine (CAF 145.1 (6.7-851.0) p<smlcap>M</smlcap>; creatinine 1.6 (0.7-8.0) mg/dl). CAF concentrations at POD 1-3 were significantly associated with DGF and outperformed creatinine in early detection of DGF (area under the curve (AUC) CAF 80.7% (95% CI 72.3-89.1%) vs. AUC creatinine 71.3% (95% CI 61.8-81.1%), p = 0.061). Conclusion: CAF is a promising new and fast biomarker for kidney function and may serve as a new tool for the early detection of DGF.

Immunosuppression in Renal Transplantation and Dyslipidemia, Which Factors Should Be Considered?

Dear Editor, Secondary dyslipidemia is the most common form of lipid metabolism derangement, due to the fact that primitive dyslipidemia represent only 0.5-2% of cases (1). Transplantation is a common cause of dyslipidemia, it has been shown that it defines metabolic syndrome, a common finding in renal transplant recipients (RTR) (2), and statins are within the top 15 drugs used by these patients (3). Moreover the increasing prescription of statins in this population is related to the frequent screening for dyslipidemia in transplanted patients (3). Immunosuppression could cause hypercholesterolemia and Cyclosporine (CsA) is widely used as immunosuppressive drug even if in the recent years physicians prescribe more frequently Tacrolimus than CsA (3). Moreover renal function in RTR is reduced and in many causes they are long-term treated with steroids. An additional risk factor for dyslipidemia should be taken into account in RTR such as chronic kidney disease, a condition in which triglycerides are increased and HDL-cholesterol is reduced. The main causes of these alterations are increased plasma levels of VLDL, IDL, LDL, Lp(a) and reduced activity of hepatic triglyceride lipase and peripheral lipoprotein lipase (4). Hypercholesterolemia secondary to steroids is due to hyperinsulinemia and peripheral insulin resistance increases hepatic synthesis of VLDL, moreover steroids reduce the release of ACTH with up-regulation of LDL-cholesterol hepatic receptors (5). On the contrary, the mechanism responsible for hypercholesterolemia during CsA treatment is still a matter of debate. CsA is a lipophilic drug and is carried by HDL and LDL cholesterol; it has been suggested that the drug impairs hepatic clearance of LDL (6). Moreover hepatic sterol regulatory element binding protein-2 is activated leading to increased VLDL synthesis, and secretion of bile and bile salts is impaired causing reduced cholesterol elimination (7). Hosseini et al. (8) study evaluated the relationship between CsA and dyslipidemia in RTR; they showed that plasma levels of cholesterol and triglycerides started increasing 4-12 months after beginning of immunosuppressive therapy, while subsequently HDL-cholesterol decreased and LDL-cholesterol increased. Logistic regression analysis showed that female gender and serum creatinine were the major risk factors for hypercholesterolemia and hypertriglyceridemia; on the contrary, CsA was not related to them. Similar results were shown by Laufer et al. (9) in heart transplant recipients. In their study the main risk factors were the history of cardiac disease leading to transplantation and steroids therapy. Hricik et al. (10) evaluated RTR and showed that reduction of steroid’s dose caused decreasing total plasma cholesterol levels. Cardiovascular disease is a major problem in RTR due to its relationship with morbidity and mortality and graft loss. Statins seem to have a protective effect in RTR, especially on risk of major cardiac events and they need to be considered during patients follow-up (4).

Blood pressure measurements, blood pressure variability and endothelial function in renal transplant recipients

Background/Aims: Hypertension is an important cardiovascular risk factor in renal transplant recipients. Elevated blood pressure variability (BPV) during 24-h ambulatory blood pressure monitoring (ABPM) is associated with increased risk of target organ damage and cardiovascular events, independent of mean blood pressure levels. We aimed to evaluate the relationship between endothelial function, blood pressure levels obtained by various measurement methods, and BPV in renal transplant recipients.Methods: In total, 73 hypertensive renal transplant recipients were included in the study. Office blood pressure measurements, central blood pressure measurements, home blood pressure measurements and 24-h ABPM were obtained from the subjects. BPV was calculated using the average real variability index. All patients underwent brachial flow-mediated vasodilatation tests. Predictive values of blood pressures obtained by different measurement techniques and BPV on endothelial functions were investigated.Results: Endothelial dysfunction was present in 68.5% of the patients. No difference was found between the group with and without endothelial dysfunction with regard to office systolic or diastolic blood pressure, central blood pressure or home systolic blood pressure. In the group with endothelial dysfunction, 24-h ambulatory systolic blood pressure and night-time ambulatory systolic blood pressure were higher. In patients with endothelial dysfunction, the 24-h systolic, diastolic and mean BPV were all higher. There was also a negative correlation between the percentage of flow-mediated vasodilatation with 24-h mean and systolic BPV.Conclusion: Patients with endothelial dysfunction had significantly higher ambulatory blood pressure values and higher BPV. There was a significant negative correlation between endothelial function and BPV.

Hypomagnesemia and the Risk of Death and GFR Decline in Chronic Kidney Disease

BackgroundHypomagnesemia predicts cardiovascular morbidity and mortality in the general population and accelerated loss of kidney function in renal transplant recipients and diabetics. It is associated with risk factors for cardiovascular and renal injury such as hyperaldosteronism, endothelial dysfunction, oxidative stress, insulin resistance, and hypertension. We aimed to establish the prognostic significance of hypomagnesemia for all-cause mortality and decline in estimated glomerular filtration rate (eGFR) in chronic kidney disease. MethodsBaseline parameters and serial follow-up measurements of serum creatinine were obtained in 1650 patients with chronic kidney disease and follow-up in a tertiary hospital between January 2002 and June 2011. We used Cox proportional hazards regression to assess the predictive value of magnesium for all-cause mortality and a random-effects mixed linear model for longitudinal analysis of the effect of serum magnesium on eGFR decline. ResultsAfter a median follow-up of 5.1 years, 284 deaths occurred. Higher magnesium was associated with reduced mortality (adjusted hazard ratio 0.930 per 0.1 mg/dL increase; 95% confidence interval [CI], 0.887-0.974; P = .002) after adjustment for potential confounders including age, sex, diabetes, kidney function, and hypertension. Patients with low (<1.8 mg/dL) versus high (>2.2 mg/dL) serum magnesium had a 61% increased mortality risk (adjusted hazard ratio 1.613; 95% CI, 1.113-2.338; P = .012). On average, eGFR changed by 0.934 per year (95% CI, 0.927-0.941; P <.0001) or an annual decrease of 6.6%. After adjustment for age, sex, diabetes, and hypertension, this change was modified by a factor of 1.033 (95% CI, 1.003-1.065; P = .032) per 1-mg/dL increase in baseline magnesium, corresponding to an annual eGFR decrease of 3.5%. The effect of magnesium lost significance after adjustment for additional covariates, including diuretics. ConclusionHypomagnesemia predicts mortality and kidney function decline in chronic kidney disease patients. Confounding factors and treatment effects may affect these associations. Its potential as a modifiable risk factor remains to be established.

Masked hypertension in renal transplant recipients

Purpose: Arterial hypertension is a risk factor affecting graft function in renal transplant recipients (RTRs). In pediatric RTRs, high prevalence of masked and nocturnal hypertension was reported. Most of the RTRs had a history of hypertension and some of them were normotensive at outpatient visits whereas home blood pressure (BP) levels were higher. Masked hypertension (MHT) is defined as a normal office BP but an elevated ambulatory BP. Previous reports have demonstrated the detrimental role of MHT in clinical outcomes in hypertensive patients. However, the true prevalence of MHT in RTRs is yet to be defined. Methods: A total of 113 RTRs (mean age 44 ± 16 years, 72 males, 41 females) with normal office BP (< 140/90 mmHg) were enrolled to the study from the outpatient renal transplantation clinic. Ambulatory BP monitoring (ABPM) was performed in all participants for a 24-h period. Average daytime BP values above 135 mmHg systolic and 85 mmHg diastolic were defined as MHT. Results: The prevalence of MHT in our cohort was 39% (n = 45). Fasting glucose and C-reactive protein levels were higher in patients with MHT compared with normal BP group (p = 0.02 and p = 0.04, respectively). RTRs with deceased donor type had higher prevalence of MHT than RTRs with living donor (40% vs 19%, p = 0.003). In multivariate analysis, deceased donor type could predict the MHT independent of age, gender, office systolic BP level, diabetes mellitus, serum creatinine, C-reactive protein, and glucose levels (OR = 3.62, 95% CI 1.16–11.31, p = 0.03). Conclusion: We demonstrated an increased prevalence of MHT in a typical renal transplant cohort. In addition, transplantation from a deceased donor may be a predictor of MHT. The prevalence of MHT may help to explain high rate of cardiovascular events in RTRs. Therefore, routine application of ABPM in RTRs may be plausible, particularly in RTRs with deceased donor type.

Achieving KDIGO Target for Blood Pressure is a Key Modifiable Risk Factor for Maintaining Long-term Stability of Graft Function in Renal Transplant Recipients (RTR)

Achieving KDIGO Target for Blood Pressure is a Key Modifiable Risk Factor for Maintaining Long-term Stability of Graft Function in Renal Transplant Recipients (RTR)

Evaluation of metabolic syndrome and associations with inflammation and graft function in renal transplant recipients

Cardiovascular disease (CVD) is a major determinant of mortality in renal transplant recipients (RTR). Metabolic syndrome (MS) and chronic inflammation are currently considered non traditional risk factors for cardiovascular disease. This study evaluates the frequency of these conditions their associations with graft function. To evaluate the prevalence of metabolic syndrome (MS) and inflammation and their associations with graft function in renal transplant recipients. A cross-sectional study was carried out with 200 RTR. MS was defined by the NCEP-ATP III criteria. Inflammation was assessed by CRP levels. Renal function was assessed by GFR estimation using the MDRD equation. MS occurred in 71 patients (35.5%). Patients with MS had higher CPR and decreased GFR levels. Inflammation was present in 99 patients (49.5%). Mean waist perimeter, body mass index, triglycerides and serum total cholesterol were significantly higher in inflamed patients. An association between MS and inflammation was demonstrated, 48 (67.6%) patients with MS were inflamed and among those without MS the rate of inflamed patients was 39.5% (51 patients) (p < 0.001). A significantly higher percentage of patients with MS in the group of patients in chronic renal disease stages III and IV was observed. In RTR there is a significant association among MS and inflammation. MS is negatively associated with graft function. The clinical implications of these findings must be evaluated in longitudinal studies.

Evaluation of pulmonary function in renal transplant recipients and chronic renal failure patients undergoing maintenance hemodialysis

BackgroundImpaired pulmonary function in patients on hemodialysis may be caused by an underlying pulmonary disease, however the effects of hemodialysis treatment and kidney transplantation are not well understood. Aim of the workThe aim of this study was to evaluate pulmonary function among patients with chronic renal failure (CRF) undergoing hemodialysis and patients with kidney transplant. Patients and methodsThis study was conducted on 60 subjects. They were classified into 3 groups: Hemodialysis group (HDG) included 20 patients with end stage renal disease (ESRD) on regular hemodialysis for at least six months and were clinically stable. Transplant group (TG) included 20 patients who had undergone kidney transplant at least six months earlier and were also clinically stable. Control group (CG) included 20 apparently healthy subjects. All subjects underwent pulmonary function testing; including resting spirometry included flow volume loop and Maximal Voluntary Ventilation (MVV), measurement of lung volumes and diffusing capacity for carbon monoxide (DLCO) using single breath technique, Six Minute Walking Test (6MWT) and arterial blood gases (ABG). ResultsThere was a significant difference between HDG, TG and CG regarding FVC% of predicted, FEV1% of predicted, FEF 25–75% of predicted, PEFR% of predicted and MVV% of predicted. Also there was a statistically significant difference between HDG, TG and CG regarding RV% of predicted, TLC% of predicted and RV/TLC%. Although FVC% of predicted and FEV1% of predicted were within the normal range in the 3 studied groups, there was a statistically significant reduction in these spirometric parameters in HDG more than that in the TG and CG, also reduction in TG more than CG. FEF 25–75% of predicted was less than normal in HDG and was within the normal range in TG and CG, also RV% of predicted and TLC% of predicted were increased in HDG more than that in TG and CG. Regarding DLco% of predicted we found significant differences between the 3 studied groups. It was lower in HDG than in TG and CG. Also the same results we found regarding Dlco/VA% of predicted. There were statistically significant differences among the studied groups regarding 6MWT. Regarding ABG although all values were within normal levels, Pao2 in HDG was less than that in TG and CG. ConclusionThere is impairment of lung function in patients with CRF undergoing hemodialysis. The main changes are small airway obstruction, reduction in carbon monoxide transfer and diminished 6MWT that were not completely improved in the kidney transplant patients.