Cardiovascular disease in the kidney transplant recipient: epidemiology, diagnosis and management strategies.

Kidney transplantation (KT) is the optimal therapy for end-stage kidney disease (ESKD), resulting in significant improvement in survival as well as quality of life when compared with maintenance dialysis. The burden of cardiovascular disease (CVD) in ESKD is reduced after KT; however, it still remains the leading cause of premature patient and allograft loss, as well as a source of significant morbidity and healthcare costs. All major phenotypes of CVD including coronary artery disease, heart failure, valvular heart disease, arrhythmias and pulmonary hypertension are represented in the KT recipient population. Pre-existing risk factors for CVD in the KT recipient are amplified by superimposed cardio-metabolic derangements after transplantation such as the metabolic effects of immunosuppressive regimens, obesity, posttransplant diabetes, hypertension, dyslipidemia and allograft dysfunction. This review summarizes the major risk factors for CVD in KT recipients and describes the individual phenotypes of overt CVD in this population. It highlights gaps in the existing literature to emphasize the need for future studies in those areas and optimize cardiovascular outcomes after KT. Finally, it outlines the need for a joint 'cardio-nephrology' clinical care model to ensure continuity, multidisciplinary collaboration and implementation of best clinical practices toward reducing CVD after KT.

Intragraft Molecular Pathways Associated with Tolerance Induction in Renal Transplantation.

The modern immunosuppression regimen has greatly improved short-term allograft outcomes but not long-term allograft survival. Complications associated with immunosuppression, specifically nephrotoxicity and infection risk, significantly affect graft and patient survival. Inducing and understanding pathways underlying clinical tolerance after transplantation are, therefore, necessary. We previously showed full donor chimerism and immunosuppression withdrawal in highly mismatched allograft recipients using a bioengineered stem cell product (FCRx). Here, we evaluated the gene expression and microRNA expression profiles in renal biopsy samples from tolerance-induced FCRx recipients, paired donor organs before implant, and subjects under standard immunosuppression (SIS) without rejection and with acute rejection. Unlike allograft samples showing acute rejection, samples from FCRx recipients did not show upregulation of T cell- and B cell-mediated rejection pathways. Gene expression pathways differed slightly between FCRx samples and the paired preimplantation donor organ samples, but most of the functional gene networks overlapped. Notably, compared with SIS samples, FCRx samples showed upregulation of genes involved in pathways, like B cell receptor signaling. Additionally, prediction analysis showed inhibition of proinflammatory regulators and activation of anti-inflammatory pathways in FCRx samples. Furthermore, integrative analyses (microRNA and gene expression profiling from the same biopsy sample) identified the induction of regulators with demonstrated roles in the downregulation of inflammatory pathways and maintenance of tissue homeostasis in tolerance-induced FCRx samples compared with SIS samples. This pilot study highlights the utility of molecular intragraft evaluation of pathways related to FCRx-induced tolerance and the use of integrative analyses for identifying upstream regulators of the affected downstream molecular pathways.

Macrocycle conformational sampling with MacroModel.

Sampling low energy conformations of macrocycles is challenging due to the large size of many of these molecules and the constraints imposed by the macrocycle. We present a new conformational search method (implemented in MacroModel) that uses brief MD simulations followed by minimization and normal-mode search steps. The method was parametrized using a set of 100 macrocycles from the PDB and CSD. It was then tested on a publicly available data set for which there are published results using alternative methods; we found that when the same force field is used (in this case MMFFs in vacuum), our method tended to identify conformations with lower energies than what the other methods identified. The performance on a new set of 50 macrocycles from the PDB and CSD was also quite good; the mean and median RMSD values for just the ring atoms were 0.60 and 0.33 Å, respectively. However, the RMSD values for macrocycles with more than 30 ring-atoms were quite a bit larger compared to the smaller macrocycles. Possible origins for this and ideas for improving the performance on very large macrocycles are discussed.

Post-transplant Lymphoproliferative Disorder--a case of late-onset T-cell lymphoma after failed renal transplant.

Post-transplant lymphoproliferative disease (PTLD) is a rare but life-threatening complication after solid organ transplantation. The risk of PTLD varies with recipient age, serostatus of the donor and the recipient for Epstein-Barr virus, type of organ transplanted, and intensity of immunosuppression. The risk of PTLD is highest in the early post-transplant period, but the cumulative risk increases with time. We report a case of PTLD occurring 17 years after renal transplantation in a 59-year-old woman.

ConfGen: a conformational search method for efficient generation of bioactive conformers.

We describe the methodology, parametrization, and application of a conformational search method, called ConfGen, designed to efficiently generate bioactive conformers. We define efficiency as the ability to generate a bioactive conformation within a small total number of conformations using a reasonable amount of computer time. The method combines physics-based force field calculations with empirically derived heuristics designed to achieve efficient searching and prioritization of the ligand's conformational space. While many parameter settings are supported, four modes spanning a range of speed and quality trades-offs are defined and characterized. The validation set used to test the method is composed of ligands from 667 crystal structures covering a broad array of target and ligand classes. With the fastest mode, ConfGen uses an average of 0.5 s per ligand and generates only 14.3 conformers per ligand, at least one of which lies within 2.0 A root-mean-squared deviation of the crystal structure for 96% of the ligands. The most computationally intensive mode raises this recovery rate to 99%, while taking 8 s per ligand. Combining multiple search modes to "fill-in" holes in the conformation space or energy minimizing using an all-atom force field each lead to improvements in the recovery rates at higher resolutions. Overall, ConfGen is at least as good as competing programs at high resolution and demonstrates higher efficiency at resolutions sufficient for many downstream applications, such as pharmacophore modeling.

Statin therapy in South Asians-facts and future.

South Asians have higher overall burden of coronary heart disease. South Asian migrants suffer from more severe and fatal coronary heart disease at younger age despite similar risk factors compared with local population. Elevated blood cholesterol contributes to atherosclerosis and heart disease and is one of the primary modifiable risk factor for these conditions. Since the discovery of a fungal metabolite that inhibits 3-hydroxy-3methyl-glutaryl-coenzyme A reductase, statins have emerged rapidly as the global leader in medical therapeutics designed to lower low-density lipoprotein cholesterol and had reduced mortality and morbidity from coronary heart disease when used for primary or secondary prevention. Despite the considerable burden imposed by cardiovascular disease, South Asians remain inadequately targeted for risk-reduction strategies, including screening and treatment for dyslipidemia.

Dialysis disequilibrium syndrome: a narrative review.

Dialysis Disequilibrium Syndrome (DDS) is characterized by neurological symptoms caused by rapid removal of urea during hemodialysis. It develops primarily from an osmotic gradient that develops between the brain and the plasma as a result of rapid hemodialysis. This results in brain edema that manifests as neurological symptoms such as headache, nausea, vomiting, muscle cramps, tremors, disturbed consciousness, and convulsions. In severe cases, patients can die from advanced cerebral edema. Recent advancements in cell biology implicate the role of urea disequilibrium (with a smaller contribution from organic osmolytes) as the pathophysiological mechanism responsible for this syndrome. In this review, we discuss the pathogenesis, clinical features and prevention of DDS.

Isolated pleural effusion as a presentation of high cardiac output heart failure in a hemodialysis patient.

Congestive heart failure is a well-recognized complication of hemodialysis arteriovenous fistula. Symptoms of dyspnea are usually associated with signs of congestive heart failure including pulmonary edema, pleural effusions, lower extremity edema, and liver enlargement, to name a few. We present a case of a gentleman with end-stage renal disease on chronic hemodialysis, which developed acute bilateral transudative pleural effusions in the absence of other signs of systemic venous congestion, associated with pulmonary venous congestion. We also discuss the pathogenesis and role of hemodialysis in management of this patient.

Decompensated high-output congestive heart failure in a patient with AVF and the role of right heart catheterization: a case study.

A 70-year-old Caucasian male presented 8 months postcadaveric renal transplant with slowly progressive shortness of breath, abdominal distention, and cough for a duration of a few days. Thorough evaluation found him to have severe pulmonary hypertension (PH) on echocardiogram with decompensated high-output congestive heart failure. A right heart catheterization was done, which confirmed elevated right-sided pressures and high cardiac output. The mean pulmonary artery pressure, on a Swan-Ganz catheter, improved from 37 to 30 mmHg on partial manual occlusion of his still functioning hemodialysis arteriovenous fistula. Subsequently, the patient underwent ligation of the fistula and this led to gradual improvement in his symptoms. Follow-up right heart catheterization and echocardiogram showed marked improvement and normalization of right heart pressures. We recommend that patients with arteriovenous fistula should undergo close monitoring for development of early signs and symptoms of congestive heart failure and screening for PH by echocardiography post-kidney transplant. Right heart catheterization should be considered if screening is positive. Risk and benefit of fistula closure should be weighed in face of reduced survival from PH in dialysis patients and closure should be considered in post-transplant patients.

Long-term kidney allograft function and survival in prednisone-free regimens: tacrolimus/mycophenolate mofetil versus tacrolimus/sirolimus.

BACKGROUND AND OBJECTIVES: The optimal maintenance immunosuppressive regimen to improve long-term renal allograft function and graft survival is yet to be determined. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This observational study prospectively compared tacrolimus/sirolimus with tacrolimus/mycophenolate mofetil in renal transplant recipients using a prednisone-free regimen with over 8.5 years of follow-up. Patients received methylprednisonlone and anti-IL2 receptor antagonist (Basiliximab) induction and were blindly randomized to either the tacrolimus/mycophenolate mofetil (n=45) or tacrolimus/sirolimus (n=37) groups. Outcome measures included patient and renal allograft survival, incidence of acute rejection, and estimated GFR. RESULTS: The tacrolimus/mycophenolate mofetil group compared with the tacrolimus/sirolimus group had overall better renal allograft survival (91% versus 70%, P=0.02); 13 patients (35.1%) in the tacrolimus/sirolimus group and 8 patients (17.8%) in the tacrolimus/mycophenolate mofetil group experienced biopsy-proven acute cellular rejection (P=0.07). By 3 months post-transplant, estimated GFR was significantly lower in the tacrolimus/sirolimus group compared with the tacrolimus/mycophenolate mofetil group (47.7 versus 59.6 ml/min per 1.73 m(2), P=0.0002), and this trend persisted throughout the follow-up period. Also, the slope of decline in the tacrolimus/sirolimus group was significantly steeper than in the tacrolimus/mycophenolate mofetil group. CONCLUSIONS: This study shows that, in a prednisone-free immunosuppressive regimen, long-term renal graft survival and function are significantly worse in the tacrolimus/sirolimus group than the tacrolimus/mycophenolate mofetil group. The synergistic nephrotoxic effect and higher acute rejection rates in the tacrolimus/sirolimus compared with the tacrolimus/mycophenolate mofetil group adversely affect graft survival.

In Peritoneal Dialysis, Is There Sufficient Evidence to Make "PD First" Therapy?

Since its introduction more than 3 decades ago, the use of peritoneal dialysis (PD) has increased greatly due to its simplicity, convenience, and low cost. Advances in technique, antibiotic prophylaxis, and the introduction of newer solutions have improved survival, quality of life, and reduced rate of complications with PD. In Hong Kong, approximately 80% end-stage renal disease (ESRD) patients perform PD; in others, that is, Canada, Australia, and New Zealand, 20%-30% patients use PD. However, in the United States, the annual rate of prevalent patients receiving PD has reduced to 8% from its peak of 15% in mid-1980s. PD as the initial modality is being offered to far less patients than hemodialysis (HD), resulting in the current annual incidence rate of less than 10% in USA. There are many reasons preventing the PD first initiative including the increased numbers of in-center hemodialysis units, physician comfort with the modality, perceived superiority of HD, risk of peritonitis, achieving adequate clearances, and reimbursement incentives to providers. Patient fatigue, membrane failure, and catheter problems are other reasons which discourage PD utilization. In this paper, we discuss the available evidence and provide rationale to support PD as the initial renal replacement modality for ESRD patients.

Hemodialysis catheter related rhodococcus bacteremia in immunocompetent host.

Rhodococcus equi (R. equi) is an uncommon cause of infection in immunocompetent individuals. We describe a case of R. equi bacteremia associated with hemodialysis (HD) catheter in an immunocompetent patient. A 38-year-old female with end-stage renal disease (ESRD) of uncertain etiology, on HD for the past 15 months who was previously healthy otherwise, was admitted with the complaints of intermittent fever, mild nausea and occasional vomiting for two weeks. Last HD was performed four days earlier through a tunneled right internal jugular permacath. Clinically the patient was afebrile and in no acute distress. She was hemodynamically stable with no peripheral stigmata of an endovascular infection. Physical examination was essentially normal. Initially, the patient was treated with intravenous vancomycin with each HD, retaining the catheter. However, due to persistently positive blood cultures, HD catheter had to be removed. The patient became afebrile and nausea and vomiting resolved. She improved clinically, and repeated surveillance blood cultures done after the removal of catheter were reported negative. Subsequently, a new HD catheter was inserted for her. Although R. equi is an uncommon cause of infection in immunocompetent individuals, it does occur with considerable mortality and morbidity, and a high index of clinical suspicion is required to recognize this infection in immunocompetent individuals.

Adenosine triphosphate depletion by cyanide results in a Na(+)-dependent Mg(2+) extrusion from liver cells.

Addition of NaCN to isolated hepatocytes results in a marked and rapid decrease in cellular adenosine triphosphate (ATP) content, and in the extrusion of a sizable amount of cellular Mg(2+). This extrusion starts after a 10-minute lag phase and reaches a maximum of 35 to 40 nmol Mg(2+) per milligram protein within 60 minutes from the addition of CN(-). A quantitatively similar Mg(2+) extrusion is also observed after the addition of the mitochondrial uncoupler carbonyl cyanide p-trifluoromethoxy-phenylhydrazone but not that of the glycolysis inhibitor iodoacetate. The Mg(2+) extrusion is completely inhibited by the removal of extracellular Na(+) or the addition of imipramine, quinidine, or glibenclamide, whereas it persists after the removal of extracellular Ca(2+) or K(+), or the addition of amiloride. An acidic extracellular pH or the removal of extracellular HCO3⁻ inhibits the cyanide-induced Mg(2+) extrusion by at least 80%. Taken together, these data suggest that the decrease in cellular adenosine triphosphate content removes a major Mg(2+) complexing agent from the hepatocyte and results in an extrusion of hepatic Mg(2+) exclusively through a Na(+)-dependent exchange mechanism modulated by acidic changes in extracellular pH.

Mycophenolate mofetil: safety and efficacy in the prophylaxis of acute kidney transplantation rejection.

Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is an inhibitor of inosine monophosphate dehydrogenase (IMPDH). It preferentially inhibits denovo pathway of guanosine nucleotide synthesis in T and B-lymphocytes and prevents their proliferation, thereby suppresses both cell mediated and humoral immune responses. Clinical trials in kidney transplant recipients have shown the efficacy of MMF in reducing the incidence and severity of acute rejection episodes. It also improves long term graft function as well as graft and patient survival in kidney transplant recipients. MMF is useful as a component of toxicity sparing regimens to reduce or avoid exposure of steroids or calcineurin inhibitor (CNI). Enteric-coated mycophenolate sodium (EC-MPS) can be used as an alternative immunosuppressive agent in kidney transplant recipients with efficacy and safety profile similar to MMF.

Family 18 chitolectins: comparison of MGP40 and HUMGP39.

Glycosidase and lectins both bind sugars, but only the glycosidases have catalytic activity. The glycosidases occur among over 100 evolved protein families and Family 18 is one of the two chitinases (EC 3, 2.1.14) families. Interestingly, lectins are also in this evolutionary group of Family 18 glycosidase proteins. The proteins belonging to the enzymatically inactive class are referred to as chitolectins and have a binding site that is highly similar to the catalytic Family 18 enzymes. We present a comparison of the recently obtained structures of two Family 18 chitolectins, MGP40 [A.K. Mohanty, G. Singh, M. Paramasivam, K. Saravanan, T. Jabeen, S. Sharma, S. Yadav, P. Kaur, P. Kumar, A. Srinivasan, T.P. Singh, Crystal structure of a novel regulatory 40kDa mammary gland protein (MGP-40) secreted during involution, J. Biol. Chem. 278 (2003) 14451-14460.] and HumGP39 [F. Fusetti, T. Pijning, K.H. Kalk, E. Bos, B.W. Dijkstra, Crystal structure and carbohydrate-binding properties of the human cartilage glycoprotein-39, J. Biol. Chem. 278 (2003) 37753-37760; D.R. Houston, D.R. Anneliese, C.K. Joanne, D.M.V. Aalten, Structure and ligand-induced conformational change of the 39kDa glycoprotein from human articular chondrocytes, J. Biol. Chem. 278 (2003) 30206-30212.] with a focus on the glycosidase active site. We compare the sequence and the structure of these two Family 18 protein classes. The difference between the active and inactive protein is a glutamic acid which acts as the essential acid/base residue for chitin cleavage and is replaced with leucine or glutamine in the chitolectins. Furthermore, a mechanism for the interaction between the chitolectin and oligosaccharides was proposed.

Antifreeze proteins at the ice/water interface: three calculated discriminating properties for orientation of type I proteins.

Antifreeze proteins (AFPs) protect many plants and organisms from freezing in low temperatures. Of the different AFPs, the most studied AFP Type I from winter flounder is used in the current computational studies to gain molecular insight into its adsorption at the ice/water interface. Employing molecular dynamics simulations, we calculate the free energy difference between the hydrophilic and hydrophobic faces of the protein interacting with ice. Furthermore, we identify three properties of Type I "antifreeze" proteins that discriminate among these two orientations of the protein at the ice/water interface. The three properties are: the "surface area" of the protein; a measure of the interaction of the protein with neighboring water molecules as determined by the number of hydrogen bond count, for example; and the side-chain orientation angles of the threonine residues. All three discriminants are consistent with our free energy results, which clearly show that the hydrophilic protein face orientations toward the ice/water interface, as hypothesized from experimental and ice/vacuum simulations, are incorrect and support the hypothesis that the hydrophobic face is oriented toward the ice/water interface. The adsorption free energy is calculated to be 2-3 kJ/mol.

Molecular dynamics simulation studies of the effect of phosphocitrate on crystal-induced membranolysis.

In this study, following our earlier work on calcium pyrophosphate dihydrate (CPPD) crystal-induced membranolysis, we demonstrate, using the CHARMM method of molecular dynamics simulation, the protective role of phosphocitrate (PC) against solvated dimyristoyl phosphatidylcholine phospholipid bilayer disintegration on contact with the CPPD crystal. Our molecular dynamics simulations studies show that coverage of the CPPD crystal with a layer of phosphocitrate molecules results in the conservation of phospholipid bilayer integrity. We show that the rupture of the lipid bilayer in presence of CPPD and the protective effect of PC are primarily due to electrostatic interactions. The protective role of PC, which may also play an important and potentially therapeutic function against crystal-induced membranolysis is also discussed.