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Cytomegalovirus (CMV) infection remains a common infection after solid-organ transplantation. In the general population CMV disease is associated with Guillain–Barre syndrome (GBS), an autoimmune disease leading to an acute peripheral neuropathy, in 1 of 1000 cases. Interestingly, GBS is a rarely observed complication in solid-organ transplant recipients, possibly related to maintenance immunosuppression. We describe a case of CMV infection complicated by GBS in a kidney transplant recipient and review the literature.

ObjectivesTo evaluate the efficacy and safety of avacopan in the subgroup of patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis receiving background induction therapy with rituximab in the phase 3 ADVOCATE trial.MethodsKey efficacy outcomes were remission at week 26 and sustained remission at week 52. Additional outcomes included the Glucocorticoid Toxicity Index, estimated glomerular filtration rate, urinary albumin to creatinine ratio, health-related quality of life and safety.ResultsOf the 330 patients who received study medication, 214 (64.8%) received rituximab (once weekly for 4 weeks), with a mean age of 59.8 years; 163 (76.2%) had renal vasculitis and 125 (58.4%) were newly diagnosed. Remission at week 26 and sustained remission at week 52 were achieved by 83/107 (77.6%) and 76/107 (71.0%) patients in the avacopan group and 81/107 (75.7%) and 60/107 (56.1%) in the prednisone taper group, respectively. The relapse rate, recovery of renal function, speed of reduction in albuminuria and glucocorticoid toxicity favoured the avacopan group. Serious adverse events occurred in 34.6% and 39.3% of patients in the avacopan and prednisone taper groups, respectively.ConclusionsThese data suggest that in patients with ANCA-associated vasculitis receiving rituximab, efficacy of treatment with avacopan compared with a prednisone taper was similar at week 26 and greater at week 52, with a favourable safety profile. In addition, avacopan was associated with improved renal outcomes and lower glucocorticoid toxicity. These results demonstrate the efficacy and safety of avacopan in patients receiving background induction therapy with rituximab.Trial registration number NCT02994927.

Treatment of hyperhomocysteinemia in hemodialysis patients and renal transplant recipients. Hyperhomocysteinemia, a putative atherothrombotic risk factor, is observed in at least 85% of patients undergoing maintenance hemodialysis (HD), as well as 65 to 70% of renal transplant recipients (RTRs). The hyperhomocysteinemia regularly found in HD patients is largely refractory to combined oral vitamin B supplementation featuring supraphysiological doses of folic acid (FA). Relative to their HD counterparts, the hyperhomocysteinemia of RTRs appears to be considerably less refractory to treatment with high-dose FA-based vitamin B supplementation regimens, although controlled comparison data are lacking. We evaluated whether improved total homocysteine (tHcy)-lowering efficacy could be achieved in chronic HD patients with a high-dose L-5-methyl-tetrahydrofolate (MTHF)-based regimen, as suggested by recent uncontrolled findings, and compared the relative responsiveness of RTRs and HD patients with equivalent baseline tHcy levels, to 12 weeks of tHcy lowering with combined folate-based vitamin B treatment. First, we blocked randomized 50 chronic, stable HD patients based on their screening predialysis tHcy levels, sex, and dialysis center into two groups of 25 subjects treated for 12 weeks with oral FA at 15 mg/day, or an equimolar amount (17 mg/day) of oral MTHF. All 50 subjects also received 50 mg/day of oral vitamin B6 and 1.0 mg/day of oral vitamin B12. The mean percentage (%) reductions (± 95% confidence intervals) in predialysis tHcy were not significantly different [MTHF 17.0% (12.0 to 22.0%), FA 14.8% (9.6 to 20.1%),P = 0.444 by matched analysis of covariance adjusted for pretreatment tHcy]. Final on-treatment values (mean with 95% confidence interval) were: MTHF, 20.0 μmol/L (18.8 to 21.2); and FA, 19.5 μmol/L (18.3 to 20.7). Moreover, neither treatment resulted in “normalization” of tHcy levels (that is, final on-treatment values <12 μmol/L) among a significantly different or clinically meaningful number of patients [MTHF, 2 out of 25 (8%); FA, 0 out of 25 (0%); Fisher's exact test of between groups difference,P = 0.490]. Second, we compared the relative responsiveness of (N = 10) RTRs and (N = 39) HD patients with equivalent baseline tHcy levels (RTR range of 14.2 to 23.6 μmol/L, and HD range of 14.4 to 24.9 μmol/L) to 12 weeks of tHcy-lowering treatment. The RTRs received 2.4 mg/day of FA, 50.0 mg/day of vitamin B6, and 0.4 mg/day of vitamin B12, while the HD patients received 15 mg/day of FA or an equmolar amount (17 mg/day) of the reduced folate, MTHF, in addition to 50.0 mg/day of vitamin B12. The mean percentage (%) reductions (± 95% confidence interval) in tHcy were as follows: RTR 28.1% (16.2 to 40.0%); HD 12.1% (6.6 to 17.7%,P = 0.027 for comparison of between groups differences by analysis of covariance adjusted for baseline tHcy levels). Moreover, 5 out of 10 (50.0%) of the RTR versus only 2 out of 39 (5.1%) of the HD patients had final on-treatment tHcy levels <12 μmol/L <12 μmol/L (P = 0.002 for comparison of between groups differences by Fisher's exact test). First, in comparison to hgh-dose FA, high-dose oral MTHF-based supplementation does not afford improved tHcy-lowering efficacy among HD patients. The preponderance of HD patients (that is, > 90%) exhibits mild hyperhomocysteinemia refractory to treatment with either regimen. This treatment refractoriness is not related to defects in folate absoprption or circulating plasma and tissue distribution. Second, relative to RTR with comparable baseline tHcy levels, the mild hyperhomocysteinemia of maintenance HD patients is much more refractory to tHcy-lowering vitamin B treatment regimens featuring suprahysiological amounts of FA or the reduced folate MTHF. Accordingly, RTRs are a preferable target population for controlled clinical trials testing the hypothesis that tHcy-lowering vitamin B intervention may reduce arteriosclerotic cardiovascular disease event rates in patients with chronic renal disease.

Bone disease remains a major cause of morbidity after renal transplantation. Post-transplant osseous complications include osteoporosis and osteonecrosis, both historically associated with glucocorticoids, and a newer syndrome of bone pain associated with calcineurin inhibitors. Calcineurin inhibitor-induced pain syndrome (CIPS) is a reversible etiology of lower extremity bone pain and bone marrow edema reported in patients receiving cyclosporine or tacrolimus after solid organ or bone marrow transplantation. While the syndrome’s pathophysiology is unclear, bone insufficiency and epiphyseal impaction may play a role. We review the literature on this increasingly important post-transplant entity and describe a case illustrating the syndrome’s key features.

Patients with diabetes mellitus might be at a higher risk of HMG-CoA reductase inhibitor (statin)-induced myotoxicity, possibly because of reduced clearance of the statin lactone. The present study was designed to investigate the effect of diabetes on the biotransformation of atorvastatin acid, both in vivo in nondiabetic and diabetic renal transplant recipients, and in vitro in human liver samples from nondiabetic and diabetic donors. A total of 312 plasma concentrations of atorvastatin acid and atorvastatin lactone, from 20 nondiabetic and 32 diabetic renal transplant recipients, were included in the analysis. Nonlinear mixed-effects modelling was employed to determine the population pharmacokinetic estimates for atorvastatin acid and atorvastatin lactone. In addition, the biotransformation of these compounds was studied using human liver microsomal fractions obtained from 12 nondiabetic and 12 diabetic donors. In diabetic patients, the plasma concentration of atorvastatin lactone was significantly higher than that of atorvastatin acid throughout the 24-hour sampling period. The optimal population pharmacokinetic model for atorvastatin acid and atorvastatin lactone consisted of a two- and one-compartment model, respectively, with interconversion between atorvastatin acid and atorvastatin lactone. Parent drug was absorbed orally with a population estimate first-order absorption rate constant of 0.457 h(-1). The population estimates of apparent oral clearance (CL/F) of atorvastatin acid to atorvastatin lactone, intercompartmental clearance (Q/F), apparent central compartment volume of distribution after oral administration (V(1)/F) and apparent peripheral compartment volume of distribution after oral administration (V(2)/F) for atorvastatin acid were 231 L/h, 315 L/h, 325 L and 4910 L, respectively. The population estimates of apparent total clearance of atorvastatin lactone (CL(M)/F), apparent intercompartmental clearance of atorvastatin lactone (Q(M)/F) and apparent volume of distribution of atorvastatin lactone after oral administration (V(M)/F) were 85.4 L/h, 166 L/h and 249 L, respectively. The final covariate model indicated that the liver enzyme lactate dehydrogenase was related to CL/F and alanine aminotransferase (ALT) was related to Q/F. Importantly, diabetic patients have 3.56 times lower CL(M)/F than nondiabetic patients, indicating significantly lower clearance of atorvastatin lactone in these patients. Moreover, in a multivariate population pharmacokinetics model, diabetes status was the only significant covariate predicting the values of the CL(M)/F. Correspondingly, the concentration of atorvastatin acid remaining in the microsomal incubation was not significantly different between nondiabetic and diabetic liver samples, whereas the concentration of atorvastatin lactone was significantly higher in the samples from diabetic donors. In vitro studies, using recombinant enzymes, revealed that cytochrome P450 (CYP) 3A4 is the major CYP enzyme responsible for the biotransformation of atorvastatin lactone. These studies provide compelling evidence that the clearance of atorvastatin lactone is significantly reduced by diabetes, which leads to an increased concentration of this metabolite. This finding can be clinically valuable for diabetic transplant recipients who have additional co-morbidities and are on multiple medications.

A renal transplant recipient with a remote history of end-stage renal disease due to postpartum hemolytic-uremic syndrome (HUS) presented with acute renal failure after having stable renal allograft function for 9 years. A diagnosis of thrombotic microangiopathy was made based on clinical and histologic findings at renal biopsy. She was treated conservatively, never regaining graft function and ultimately succumbing from her overwhelming tumor load approximately 6 months following diagnosis of her malignancy. To our knowledge, this is the first report of thrombotic microangiopathy associated with disseminated malignancy resulting in renal allograft failure.

Polyoma or BK virus nephropathy may lead to impaired renal function after transplantation. This opportunistic infection is a surrogate marker for over immunosuppression. Treatment consists of reduction in immunosuppression (IS); however, this increases the risk of acute allograft rejection. Recently we have estimated global immunosuppression by measuring ATP activity in stimulated CD4(+) cells(Immuknow-Cylex Inc). This assay serves as a marker of cell-mediated immunity. High levels (>525 ATP ng/ml) correspond to robust immunity and carry a heightened risk of acute rejection, while low levels (<225 ATP ng/ml) increases the risk of opportunistic infection, including Polyoma virus. We treated 4 patients with reduction in IS for Polyoma nephropathy, before we started using Immuknow monitoring. There was clearance of BK viremia in all patients, however one patient developed acute rejection 5 months after reduction of IS. Another patient lost the kidney allograft to a rapidly progressive chronic nephropathy and returned to dialysis. The remaining 3 patients have stable graft function. Immuknow assay was used to monitor IS reduction in three patients. Immunknow levels ranged from 16 to 172 at the time of detection of Polyoma nephropathy. With serial reduction in IS there was a stepwise increase in Immuknow levels and decrease in BK viremia. These preliminary data suggest that serial reduction of IS with immune monitoring is a safe approach for the treatment of polyoma nephropathy after renal transplantation.

Immunocompromised individuals (patients with cancer, diabetes, HIV/AIDS, transplant recipients) and pregnant women are at greater risk of complicated foodborne illness than the general population. Though rare, Campylobacter enteritis-associated acute pancreatitis has not been reported in an immunocompromised host to our knowledge. Herein, we describe a case of Campylobacter infection-associated pancreatitis in a renal transplant recipient. This case highlights the need for food safety education for the immunocompromised, emphasizes the role of health care providers in encouraging adherence to food safety guidelines, and stresses the need to maintain broad infectious differentials for immunocompromised patient populations, even for conditions which are not commonly associated with an infectious etiology.Immunocompromised individuals (patients with cancer, diabetes, HIV/AIDS, transplant recipients) and pregnant women are at greater risk of complicated foodborne illness than the general population. Though rare, Campylobacter enteritis-associated acute pancreatitis has not been reported in an immunocompromised host to our knowledge. Herein, we describe a case of Campylobacter infection-associated pancreatitis in a renal transplant recipient. This case highlights the need for food safety education for the immunocompromised, emphasizes the role of health care providers in encouraging adherence to food safety guidelines, and stresses the need to maintain broad infectious differentials for immunocompromised patient populations, even for conditions which are not commonly associated with an infectious etiology.