Evangelos Papachristou

Predisposing Factors to the Development of Urinary Tract Infections in Renal Transplant Recipients and the Impact on the Long-Term Graft function

Abstract Urinary tract infections (UTIs) represent the most common cause of bacterial infection in renal allograft recipients. The purpose of this study was to estimate the predisposing factors and the impact of UTIs in the long-term graft function. We studied 122 patients (75 males and 47 females), aged 44 ± 12 years. UTIs occurring during the first month, during the first year, and through the entire follow-up period were analyzed. Diabetes mellitus (DM), delayed graft function, acute rejection episodes, and urinary tract obstruction were evaluated as potential predisposing factors. UTI episodes (n = 316) were recorded in 74 of 122 patients (60.7%). The most common pathogen was Escherichia coli. Most patients (81%) who developed infection during the first month had a new episode in the first year. Hospitalization was necessary in 141 of the 316 UTI episodes whereas 87 were hospital acquired. A strong correlation between female gender and UTI occurrence was found (p = 0.01). Urinary tract obstruction was also related to the UTI occurrence during the first year after transplantation (p = 0.001). Patients’ age, DM, delayed graft function, and acute rejection episodes did not correlate with UTI. Long-term renal graft function was not found to be affected by UTI occurrence. UTIs are common infectious complications in renal transplant recipients and often relapse and require hospitalization. The long-term graft function is not affected by the occurrence of UTIs.

Randomized controlled trial comparing primary and staged basilic vein transposition

Objective It is unclear if brachio-basilic vein fistula should be performed as a primary or staged procedure, particularly for smaller basilic veins. Our aim was to report on a randomized controlled trial comparing these two techniques. Methods Sixteen patients with a basilic vein ≥2.5 mm were randomized into primary transposed brachio-basilic vein (TBBV) fistula (n = 9) and staged TBBV fistula (n = 7). Patients with basilic veins enlarged by previous arteriovenous fistulas were excluded. Baseline characteristics of the two study groups, including vein size, were comparable (median basilic vein diameter 3.5 mm, range 2.8–4.1 mm). The staged group had a brachio-basilic vein fistula performed first followed by the transposition procedure performed at least 6 weeks later to allow the basilic vein to enlarge. TBBV fistula maturation at 10 weeks, primary, assisted-primary, and secondary patency were the primary outcome measures. Early failures were included in the calculation of patency rates. Results Transposed brachio-basilic vein fistula maturation rate after primary procedures (3/9, 33%) was lower compared to maturation rate after staged procedures (7/7, 100%, P = 0.011, Fisher’s exact test), which led to premature termination of the trial. Time to hemodialysis [median (interquartile range)] of primary and staged procedures was 54 (51.5–113.5) days and 97 (93–126) days, respectively (P = 0.16). One-year primary and assisted-primary patency rates of primary and staged procedures were equivalent (44 vs 57%, P = 0.76 and 44 vs 71%, P = 0.29, respectively); however, there was a trend toward a better 1-year secondary patency after staged procedures (86 vs 44% for primary procedures, P = 0.09). Conclusions Among candidates for TBBV fistula with a small basilic vein, staged transposition achieves higher maturation rates compared to primary procedures, a difference reflected in long-term secondary patency. Trial registration www.ClinicalTrials.gov, identifier NCT01274117.

The prognostic value of frozen section preimplantation graft biopsy in the outcome of renal transplantation.

Introduction: Preimplantation biopsy provides a window on the state of the renal allograft. In this study, the prognostic value of frozen section preimplantation graft biopsy was estimated and compared to regularly processed formalin-fixed biopsy. Materials and Methods: Seventy-four renal allograft recipients were studied. The degree of glomerulosclerosis, acute tubular necrosis, interstitial fibrosis, arteriosclerosis, and arteriolosclerosis was rapidly estimated in frozen sections and correlated to the renal function in the immediate posttransplantation period and 3 months thereafter. The histological changes were also examined in paraffin-embedded sections. Results: The histological changes observed in rapidly processed frozen sections were comparable to those observed on regularly processed sections and their differences did not reach statistical significance. Glomerulosclerosis and arteriolosclerosis were underestimated, whereas acute tubular necrosis and interstitial fibrosis were overestimated, in the frozen sections compared to permanent ones, but those differences were not statistically significant. Immediate graft function was observed in 45 patients (61%). Delayed graft function was more frequently observed among recipients with donor age above 60 years (57% vs. 32%). Serum creatinine 3 months after transplantation was above 2 mg/dL in 33 recipients (44.5%) and was positively correlated to the degree of tubular necrosis (p = 0.04) and donor age (p = 0.03). Donor age was correlated to the degree of arteriolosclerosis (p < 0.01). Conclusions: Frozen section preimplantation biopsy gives reliable information for the situation of the graft that is related to the outcome of renal transplantation.

Increased Prevalence and Severity of Coronary Artery Calcification in Patients with Chronic Kidney Disease Stage III and IV.

Background: Cardiovascular disease (CVD) is the main cause of mortality in patients with chronic kidney disease (CKD). The pathophysiology of coronary artery disease in CKD is multifactorial including, in addition to traditional risk factors (hypertension, hyperlipidemia, diabetes mellitus), parameters related to uremia. Methods: The study consisted of measuring coronary artery calcification (CAC) score in patients with CKD stage III and IV without history of CVD and in a group of controls with normal renal function matched for age, gender and risk factors using multi-detector computed tomography. Results: The study included 49 patients and 49 controls. CAC was present in 79.6% in the CKD group versus 59.2% in the control group (p = 0.028). The median CAC score value in CKD patients was 139 (interquartile range (IQR): 23–321) versus 61 (IQR: 6–205) in controls (p = 0.007). CAC was associated with traditional risk factors such as older age, hypertension and baseline cardiovascular risk score, while CKD patients with severe calcification had marginally lower estimated glomerular filtration rate and increased levels of parathormone. Conclusions: CAC is more frequent and severe in patients with CKD stage III and IV compared to matched controls with normal renal function, even though kidney disease-related parameters are not directly correlated with intensity of calcification.

Cyclosporine Induces Endothelin-1 mRNA Synthesis and Nitric Oxide Production in Human Proximal Tubular Epithelial Cell Cultures

Background. Cyclosporine (CsA) is implicated in the development of chronic allograft nephropathy, which is related to reduced long-term allograft survival. The activation of tubular epithelial cells is involved in the renal scarring process via stimulation of factors such as endothelin-1 (ET-1) and nitric oxide (NO). The effect of CsA on the activation of tubular epithelial cells towards increased production of ET-1 and NO was investigated in this study. Methods. Human tubular epithelial cells (HK-2) were cultured in the presence of CsA at different concentrations (125, 250, 500, and 1,000 ng/mL). ET-1 m-RNA and NO production were measured using RT-PCR and Griess method, respectively. The cytotoxic effect of CsA was examined by the MTT method and cell count. Results. A statistically significant and dose-dependent cytotoxic effect of cyclosporine on HK-2 cells was observed. A dose-dependent up-regulation of ET-1 mRNA production and NO accumulation was observed under the influence of CsA. Conclusion. Increased synthesis of endothelin-1 mRNA and nitric oxide as well as a significant cytotoxic effect on tubular epithelial cells under the influence of CsA might be related to the development of CsA nephrotoxicity.

Optimal use of phosphate binders in chronic kidney disease

Introduction: Hyperphosphatemia is one of the major factors associated with the development of vascular calcification in patients with chronic kidney disease (CKD). Since phosphate is retained in such patients, pharmacological treatment and other measures are necessary to control hyperphosphatemia. Several phosphate binders (calcium salts, magnesium salts, non-calcium-based binders and aluminium) are available for the treatment of hyperphosphatemia. Nevertheless, none of the above mentioned agents has shown an overall superiority over others, while potency and side effects are quite variable among them creating difficulties in choosing the optimal drug for each patient. Areas covered: The authors discuss the disturbed phosphate metabolism, the available phosphate binders, as well as the general therapeutic principles of treating hyperphosphatemia in CKD patients. The literature used for this review had been retrieved from PubMed and covers a large number of original and retrospective studies as well as prospective cohort studies, meta-analyses and international clinical guidelines. Expert opinion: Lowering serum phosphate levels in CKD patients may potentially have a positive impact on cardiovascular morbidity and mortality. Factors that should be taken into consideration when selecting a specific drug include CKD stage, cardiovascular disease, severity of secondary hyperparathyroidism, concomitant medications, life expectancy and patient compliance. Therefore, when selecting a specific phosphate binder, individualisation is mandatory.

Ezetimibe is effective in the treatment of persistent hyperlipidemia of renal allograft recipients.

INTRODUCTION Ezetimibe is a hypolipidemic agent acting via inhibition of cholesterol absorption from the small intestine. The effectiveness and safety of long-term administration of ezetimibe was evaluated in renal allograft recipients with persistent hyperlipidemia. PATIENTS AND METHODS 67 renal allograft recipients with post-transplantation hyperlipidemia resistant to statins were included in the study; 11 were treated with ezetimibe (10 mg/day) alone and 56 with ezetimibe and statin. The effectiveness of ezetimibe was assessed by determination of total cholesterol (TC), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C) and triglycerides (TR). Its safety was determined by liver enzymes (ALT, AST), LDH, CPK, serum creatinine and blood levels of immunosuppressive drugs (cyclosporine, tacrolimus, everolimus, sirolimus) over the follow-up period of 18±6 months. RESULTS A significant reduction of TC and LDL-C blood levels by 25% and 34% respectively, was observed during the first month of treatment with ezetimibe (p<0.001). This reduction was maintained for the whole period of ezetimibe administration. Renal function remained stable over the follow-up period, while no changes of the blood levels of immunosuppressive drugs were observed. Liver enzymes, LDH and CPK remained normal in all patients except for one diabetic patient who developed rhabdomyolysis. Apart from gastrointestinal symptoms in 2 patients, no other side effects were observed. CONCLUSION Combination of ezetimibe with statins represents an effective and safe regimen for treatment of persistent hyperlipidemia in renal allograft recipients.

Interaction of endothelin-1 and nitric oxide pathways in human tubular epithelial cells under the influence of cyclosporine-A

Background: The exact mechanism of cyclosporine (CsA) nephrotoxicity has not been clarified. In this study, we investigated the effect of pharmacological doses of CsA on the production of nitric oxide synthases (NOSs) and endothelin (ET) receptors (ETR-A, ETR-B), in human tubular cells [human kidney (HK)-2], to identify any implication of these pathways in CsA nephrotoxicity. Methods: Human tubular epithelial cells (HK-2) were cultured in the presence of CsA at various concentrations (0–1000 ng/mL). Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to determine mRNA synthesis of NOSs (eNOS, iNOS) and ET receptors (ETR-A, ETR-B) and western blot analysis for the subsequent proteins. Results: A dose-dependent induction of synthesis of NO synthases eNOS and iNOS and ET receptors ETR-A and ETR-B was observed, even at therapeutic doses of CsA. An interaction between NO and ET-1 systems under the influence of CsA was also observed. Blockage of NO production was followed by down-regulation of ETR-B whereas blockade of ET pathway with ET receptor antagonists was followed by down-regulation of eNOS expression. Conclusion: CsA induces NOSs as well as ET receptor mRNA and protein synthesis in tubular epithelial cells. The up-regulation of NO and ET-1 pathways is probably implicated in the nephrotoxic action of CsA, whereas an interplay between ETR-B and eNOS seems to be involved.

Cytomegalovirus polyradiculopathy of late onset in a young renal transplant recipient.

Although cytomegalovirus (CMV) disease in CMV IgM/IgG-negative renal transplant recipients from CMV-positive donors (D+/R-) can occur after discontinuation of prophylaxis treatment as a flu-like syndrome or tissue invasive disease, involvement of the central nervous system is rare. Here, we report a case of CMV polyradiculopathy 6 months after renal transplantation that presented as a Guillain-Barre like syndrome and was successfully treated with foscarnet. This case highlights an uncommon aspect of CMV invasive disease which we should keep in mind in CMV (D+/R-) renal transplant recipients.

From basic anatomic configuration to maturation success

The arteriovenous fistula is the preferred vascular access for hemodialysis patients because of its low complication rate and lower costs, but it still has unacceptable failure rates. Krishnamoorthy et al. implicate the geometry of the fistula in the temporal and spatial variations occurring in two of the most important parameters of fistula maturation, blood flow and vessel diameter.