Juraj Miklušica

Cytokine and chemokine profile changes in patients with lower segment lumbar degenerative spondylolisthesis

BACKGROUND Lumbar degenerative spondylolisthesis (DS) develops as a result of inflammatory and remodeling processes in facet joints (FJs). Several inflammatory cytokines are involved in the osteoarthritic and remodeling changes that occur and in low-back and/or radicular pain, the most prevalent clinical symptom of disease. This study improves knowledge related to the roles that 27 cytokines, chemokines and growth factors play in the pathophysiology of lumbar DS. MATERIAL AND METHODS Cytokine levels were examined using capture sandwich immunoassay using the Bio-Plex® 200 System and the Bio-PlexTM Human Cytokine Standard 27-Plex, Group I (Bio-Rad, Hercules, California, USA) separately in intervertebral discs (IVDs) and FJ bone tissue. The samples were obtained during primary spinal surgery from 9 patients suffering from lower segment lumbar DS. The pain intensity was assessed using a visual analog scale. The controls were tissue samples collected from both lower lumbar segment levels of 6 male subjects during a multiorgan procurement procedure. RESULTS The Bio-Plex® assay revealed significant differences between the patients and controls in cytokines, chemokines and growth factor profiles: i, The elevated interleukin-6 (IL-6), IL-7, IL-13, tumor necrosis factor α (TNF-α), interferon γ and platelet-derived growth factor levels in lumbar DS samples of subchondral FJ bone. These indicated ongoing inflammation, bone formation and increased fibroblasts activity in the FJ bone. ii, The elevated levels of IL-6, IL-8, TNF-α, granulocyte-macrophage colony-stimulating factor and monocyte chemoattractant protein-1 in anulus fibrosus together with increased IL-6, IL-8, TNF-α and eotaxin and decreased IL-1-receptor antagonist in nucleus pulposus confirmed advanced IVD degeneration in the patient samples. CONCLUSION This study identified, for the first time, protective levels of cytokines, chemokines and growth factors in healthy subjects and supported their significant involvement in the pathogenesis of lumbar DS. The control samples and analytical methods used avoided any false changes in the cytokine levels due to secondary factors (e.g., death of donor and limited cytokine stability).

Waist Circumference as an Independent Risk Factor for NODAT

BACKGROUND New-onset diabetes mellitus after transplantation (NODAT) is a serious and frequent complication of solid organ transplantations. NODAT leads to 2-3 times higher cardiovascular morbidity and mortality. Visceral obesity is a key factor for diabetes mellitus type 2 and metabolic syndrome development, and is an independent risk factor for cardiovascular diseases. MATERIAL AND METHODS The series consisted of 167 patients after primary kidney transplantation from a dead donor (64 patients had developed NODAT), average age of the series was 46.1±11.6 years. We retrospectively examined waist circumference, body mass index, and weight gain in the 12th month after transplantation. We examined average level of triglycerides, cholesterol, and immunosuppression throughout the 12 monitored months. RESULTS Patients with NODAT were significantly older (P=0.004) and had greater waist circumference (P<0.0001) and higher average sirolimus level (P=0.0262). We identified the following independent risk factors for NODAT by using multivariate analysis: age at the time of transplantation above 50 years (HR=2.5038, [95% CI: 1.7179 to 3.6492], P<0.0001), waist circumference in men greater than 94 cm (HR=1.9492, [95% CI: 1.1697 to 3.2480], P=0.0104) and in women greater than 80 cm (HR=4.5018, [95% CI: 1.8669 to 10.8553], P=0.009). By using correlation coefficient we have proved that greater waist circumference was related to higher incidence of NODAT (r=0.1935, [95% CI: 0.01156 to 0.3630], P=0.0374). Graft survival (death censored) 12 months after kidney transplantation was 97.1% in the control group and 95.3% in the NODAT group (P=0.5381). Patient survival 12 months after kidney transplantation in the control group was 98.1% and in the NODAT group it was 96.9% (P=0.6113). CONCLUSIONS We identified waist circumference as an independent risk factor for NODAT in our analysis.

Body mass index before kidney transplantation — principal risk factor for NODAT

Purpose. Pretransplant obesity is a well-known risk factor for post-transplant outcomes such as patient and graft survival, delayed graft function, rejection, and wound complications. According to the recommendations of the European Renal Best Practice, patients who have body mass index (BMI) value of more than 30 kg/m2 before kidney transplantation should reduce their weight. Materials and methods. In the group of 297 patients who had undergone primary kidney transplantation from post-mortem donors, we found that assessed the impact of BMI on the development of new onset diabetes after transplantation (NODAT). Additionally, relationships between immunosuppression, weight gain and BMI in patients after kidney transplantation were also analysed. We measured the value of the patients’ BMI and weight before kidney transplantation, 12 months after kidney transplantation, and 5 years after kidney transplantation. The group contained only those patients who, at the time of the kidney transplantation, did not suffer from diabetes mellitus. According to the development of NODAT in the monitored period, the group of patients was divided into the control group and NODAT group. We detected analysed the data on the type of immunosuppression (tacrolimus, cyclosporine A, mTOR inhibitor) and the average levels in the monitored period and identified whether BMI or increased weight 12 months and 5 years after kidney transplantation is related to the level (or dose) of the used immunosuppression. Results. In our group, the patients who developed NODAT in the post-transplant period were significantly older in the 12-month analysis (p < 0.0001) and also in the 5-year analysis (p = 0.0001); had higher BMI at the time of transplantation (p = 0.0003) and higher BMI 12 months after kidney transplantation (p = 0.0004) and a significantly higher weight gain 12 months after kidney transplantation (p = 0.0469). We discovered that neither the level of immunosuppression nor the dose of prednisone had any effect on the increase in BMI or weight gain during the monitored period. Conclusion. The patients in the waiting list, who have any risk factors for the development of diabetes mellitus, should be informed how to eliminate these risk factors (weight control, diet, physical exercises, etc.). In addition to the above, all candidates for kidney transplantation are recommended to stop smoking, to control blood pressure, and perform a lipidogram.

The Role of Proteinuria, Paricalcitol and Vitamin D in the Development of Post-Transplant Diabetes Mellitus after Kidney Transplantation

Introduction The post-transplant diabetes mellitus (PTDM) occurs most frequently during the first year after the transplantation. We focused on parameters of calcium-phosphate metabolism and proteinuria as possible new risk factors for PTDM after kidney transplantation. Materials and Methods We have prospectively identified in a set of 167 patients after kidney transplantation risk factors for post-transplant diabetes mellitus with follow-up of 12 months. Patients with diabetes mellitus type 1 and type 2 as well as patients using ciclosporin A or mTOR inhibitor have been excluded from the monitoring. From the perspective of immunosuppression it was a homogeneous set of patients. Results We identified the following independent risk factors for PTDM in our set: average proteinuria >0,300 g/24 hours [HR 3.0785, (95 % CI 1.6946-5.5927), P = 0.0002], level of vitamin D < 20 ng/ml [HR 5.4517, (95 % CI 2.3167-11.8209), P <0.0001] base line serum level of phosphorus >1.45 mmol/l [HR0.0821, (95 % CI0.0042-1.5920), P = 0.0439]. The lowest occurrence of PTDM and proteinuria was recorded in patients whose treatment included paricalcitol (P <0.0001) and these patients had at the same time the highest level of vitamin D (P <0.0001). Figure. No caption available. Figure. No caption available. Figure. No caption available. Conclusion Deficit of vitamin D, proteinuria and hyperphosphatemia are independent risk factors for the development of PTDM in our set. We identified the usage of paricalcitol as protective factor with regard to the PTDM development.

FlowPRA Screening of antiHLA Antibodies in the Waiting List Significantly Reduces the Occurrence of Acute Rejection after Kidney Transplantation

Introduction Presence of the preformed human leukocyte antigen (HLA)–reactive antibodies in recipient serum before transplantation has long been recognized as a prominent risk factor for a generally worse graft outcome. Screening and identification of HLA antibodies can be used to stratify patients into high and low risk categories. Material and Methods This is a prospective analysis with determining the antiHLA antibodies by flowPRA (with adding the specification after positive screening – more than 5 %). According to the result of the screening test, the patient was allocated, according to the actual immunologic risk, the induction immunosuppressive protocol. Results In the group of 78 patients, we realised 2 times per year the screening of flowPRA of anti HLA antibodies. According to the immunologic risk, the patients were divided into 3 groups (low, medium, and high immunologic risk), and according to the risk, we applied the induction immunosuppressive protocol. Stratification of the risk was correct, because predicter for development of acute rejection in the monitored period of 12 months was only the late onset of the function of the donor´s graft [odds ratio 33.2501; 95% CI 10.0095-110.4508 (P < 0.0001)]. The occurrence of acute rejection upon implementing the screening was reduced in our Transplant Center from 44 % to 19 % (P < 0.0001). No difference was recorded in the 12-month survival of grafts and patients according to the applied induction immunosuppressive protocol. Conclusion We confirmed significantly reduced occurrence of acute rejection in the monitored period of 12 months in case of applying individualised induction according to flowPRA screening of antiHLA antibodies. FlowPRA represents a suitable alternative for screening and specification of antiHLA antibodies in case the Luminex methodology is unavailable. Table. No title available. Table. No title available. Table. No title available.

Leptin – A new marker for development of post-transplant diabetes mellitus?

INTRODUCTION Obese patients have increased leptin production and selective resistance to its central anti-adipogenic effects, yet its pro-inflammatory immunostimulating effects persist. MATERIAL AND METHODS In a group of 70 patients who underwent primary kidney transplantation (KT) we examined adiponectin and leptin levels at the time of KT and 6 months post-transplantation. Patients with diabetes mellitus type 1 or type 2 at the time of KT were excluded from the study. RESULTS We found that leptin levels significantly increased during the post-transplant period (P = 0.0065). Overall, leptin levels were positively correlated with the level of triacylglycerols, post-transplant diabetes mellitus (PTDM) development and acute rejection (AR). We discovered that, in particular, high leptin levels were associated with AR [OR 2.1273; 95% CI 1.0130-4.4671 (P = 0.0461)] and PTDM development [OR 7.200; 95% CI 1.0310-50.2836 (P = 0.0465)], whereas, low adiponectin levels represent a risk factor for the development of insulin resistance [HR 38.6135; 95% CI 13.3844-67.7699 (P < 0.0001)] and obesity [HR 3.0821; 95% CI 0.8700-10.9192 (P = 0.0053)]. CONCLUSION We found that a high serum concentration of leptin before KT is associated with both PTDM development and AR and merits further investigation in relation to KT.

Metabolic syndrome and new onset diabetes after kidney transplantation.

AIMS The metabolic syndrome developed after kidney transplantation is the result of several factors which are identical with the risk factors in normal population, however, also some factors typical for the transplanted patients-especially the effects of immunosuppressive therapy. MATERIAL AND METHODS In the groupof 268 patients after kidney transplantation, which had no type 1 or type 2 diabetes mellitus before transplantation, we identified patients with metabolic syndrome(based on IDF criteria), 12 months from the kidney transplantation. In all patients, we recorded the following parameters: age at the time of transplantation, type of immunosuppression, waist measure, the value of triacylglycerols, the value of HDL cholesterol, presence of arterial hypertension, andthe value of glycaemia in fasting state (or presence of diabetes mellitus). The groupof patients was divided into the control group and the group of patients with metabolic syndrome. RESULTS The average age of patients was 46.1±11.6years. The control group included 149 patients (55.6%),and we identified the metabolicsyndromein 119patients (44.4%). The patients with metabolicsyndrome were significantly older (P<0.0001), had significantly larger waist (both the entiregroup and the males andfemales) P<0.0001.The femaleswith metabolic syndrome had significantly lower value of HDL-cholesterol (P=0.0013), and significantly higher number of patients with metabolic syndrome had hyperglycaemia in fasting state or diabetes mellitus (P=0.0006). CONCLUSION By controlling the weight and waist, we may identify the risk patients for development of metabolic syndrome after kidney transplantation.

Complications of liver resection in geriatric patients

Introduction and aims. Liver resection is the treatment of choice for many primary and secondary liver diseases. Most studies in the elderly have reported resection of primary and secondary liver tumors, especially hepatocellular carcinoma and colorectal metastatic cancer. However, over the last two decades, hepatectomy has become safe and is now performed in the older population, implying a paradigm shift in the approach to these patients. MATERIAL AND METHODS We retrospectively evaluated the risk factors for postoperative complications in patients over 65 years of age in comparison with those under 65 years of age after liver resection (n = 360). The set comprised 127 patients older than 65 years (35%) and 233 patients younger than 65 years (65%). RESULTS In patients younger than 65 years, there was a significantly higher incidence of benign liver tumors (P = 0.0073); in those older than 65 years, there was a significantly higher incidence of metastasis of colorectal carcinoma to the liver (0.0058). In patients older than 65 years, there were significantly more postoperative cardiovascular complications (P = 0.0028). Applying multivariate analysis, we did not identify any independent risk factors for postoperative complications. The 12-month survival was not significantly different (younger versus older patients), and the 5-year survival was significantly worse in older patients (P = 0.0454). CONCLUSION In the case of liver resection, age should not be a contraindication. An individualized approach to the patient and multidisciplinary postoperative care are the important issues.INTRODUCTION AND AIMS Liver resection is the treatment of choice for many primary and secondary liver diseases. Most studies in the elderly have reported resection of primary and secondary liver tumors, especially hepatocellular carcinoma and colorectal meta-static cancer. However, over the last two decades, hepatectomy has become safe and is now performed in the older population, implying a paradigm shift in the approach to these patients. MATERIAL AND METHODS We retrospectively evaluated the risk factors for postoperative complications in patients over 65 years of age in comparison with those under 65 years of age after liver resection (n = 360). The set comprised 127 patients older than 65 years (35%) and 233 patients younger than 65 years (65%). RESULTS In patients younger than 65 years, there was a significantly higher incidence of benign liver tumors (P = 0.0073); in those older than 65 years, there was a significantly higher incidence of metastasis of colorectal carcinoma to the liver (0.0058). In patients older than 65 years, there were significantly more postoperative cardiovascular complications (P = 0.0028). Applying multivariate analysis, we did not identify any independent risk factors for postoperative complications. The 12-month survival was not significantly different (younger versus older patients), and the 5-year survival was significantly worse in older patients (P = 0.0454). CONCLUSION In the case of liver resection, age should not be a contraindication. An individualized approach to the patient and multidisciplinary postoperative care are the important issues.

Ureteral Stenosis of Transplanted Kidney

Abstract Introduction: Ureteral stenosis is one of the most commonly reported urological complications after kidney transplantation. Material and methods: This is a retrospective analysis of the risk factors for ureteral stenosis (type of donor, age of donor, presence of interior polar arteria, unilateral dual transplantation, diabetes mellitus of the recipient and the donor, BK positivity, child recipient, cold ischaemia time, and delayed graft function), as well as the causes and types of treating ureteral stenoses. Results: In the group of 278 patients, the occurrence was 7.2 %. The medial of occurrence of ureteral stenoses was 24.6 months. The independent risk factor for ureteral stenosis in our group was the age of the donor ≥ 70 years [HR 6.5833; 95 % CI 2.2448-19,3070 (P = 0.0006)], BK positivity [HR 13.6667; 95 % CI 6.9127-27.0196 (P<0.0001)], cold ischaemia time > 1080 min [HR 4.0368; 95 % CI 1.7250-9,4465 (P = 0.0013)], and diabetes mellitus in the donor’s history [HR 16.2667; 95 % CI 7.8629-33.6525 (P <0.0001)]. The most frequent type of treating the ureteral stenosis in our group was retroureteroneocystostomy. After surgical treatment, we recorded no recurrence of stenosis. Conclusion: In our analysis, the confirmed independent risk factor was diabetes mellitus of the donor. However, further monitoring and analyses of large groups of patients are necessary. Surgical treatment of ureteral stenosis is safe. However, the most important momentum in surgical treatment of ureteral stenosis still remains the surgeon´s experience in the given type of treatment.

Correlation between CMV Infection and NODAT

Purpose: New-onset diabetes mellitus after transplantation (NODAT) is a well-known complication of transplantation. Materials and methods: Retrospectively, we detected CMV replication (PCR) in every month after transplantation of kidney in the first 12 months after transplantation in patients in a homogenous group from the aspect of immunosuppresion. Results: In the group of 167 patients (control group: n = 103, NODAT group: n = 64), the average value of CMV viremia was without any significant difference between the NODAT group and the control group (P = 0.9285). In the 10th month after kidney transplantation, we recorded significantly higher CMV viremia in the NODAT group (p < 0.0001), however, in the multi variant analysis, that difference was not confirmed. Thus, in our group, CMV is of no relevance with the development of NODAT in the monitored period. The survival of patients and graft was 12 months after kidney transplantation without any statistically significant difference between the monitored groups (P = 0.6113 - survival of the patient; P = 0.5381 – survival of the graft). Conclusion: Our analysis shows that in regular monitoring of CMV viremia and applying chemoprophylaxison the risk recipeints, CMV is not the risk factor for NODAT.