Increased ischemic stroke, acute coronary artery disease and mortality in patients with granulomatosis with polyangiitis and microscopic polyangiitis.

OBJECTIVE: The aim of our study was to assess major cardiovascular event incidence, predictors, and mortality in ANCA-associated vasculitis (AAV). METHODS: We conducted a retrospective cohort study of all GPA or MPA, according to Chapel Hill Consensus Conference classification criteria, diagnosed between 1981 and 2015. Major cardiovascular event was defined as acute coronary artery disease, or ischemic stroke, or peripheral vascular disease requiring a revascularization procedure. We calculated the comparative morbidity/mortality figure (CMF) and we used Cox proportional hazards regression models to assess the risk of coronary artery disease, ischemic stroke associated with AAV, after adjusting for covariates. RESULTS: 125 patients, 99 GPA (79,2%) and 26 MPA (20,8%), were followed 88.4 ±â€¯78.3 months. Ischemic stroke incidence was four times higher than in the general population (CMF 4,65; 95% CI 4,06-5,31). Coronary artery disease incidence was four times higher than in the general population (CMF 4,22; 95% CI 1,52-11,68). Smoking habits and history of coronary artery disease were strongly associated with coronary artery disease occurrence (adjusted HR 8.8; 95% CI 2.12-36.56, and adjusted HR 10.3; 95% CI 1.02-104.5, respectively). ENT flare-up was an independent protective factor for coronary artery disease occurrence. We did not identify factors significantly associated with stroke occurrence. The age-adjusted mortality rate was 22.5 per 1000 person-years. Mortality in AAV was 1.5 times higher than in the general population (CMF 1.56; 95% CI 1.34-1.83). CONCLUSION: AAV have a significantly increased risk of mortality, ischemic stroke, and coronary artery disease.

Efficacy and Safety of Sofosbuvir-Based Antiviral Therapy to Treat Hepatitis C Virus Infection After Kidney Transplantation.

There is no approved therapy for hepatitis C virus (HCV) infection after kidney transplantation, and no data regarding the use of new-generation direct antiviral agents (DAAs) have been published so far. The aims of this pilot study were to assess the efficacy and safety of an interferon-free sofosbuvir-based regimen to treat chronic HCV infection in kidney transplant recipients. Twenty-five kidney transplant recipients with chronic HCV infection were given, for 12 (n = 19) or 24 weeks (n = 6), sofosbuvir plus ribavirin (n = 3); sofosbuvir plus daclatasvir (n = 4); sofosbuvir plus simeprevir, with (n = 1) or without ribavirin (n = 6); sofosbuvir plus ledipasvir, with (n = 1) or without ribavirin (n = 9); and sofosbuvir plus pegylated-interferon plus ribavirin (n = 1). A rapid virological response, defined by undetectable viremia at week 4 after starting DAA therapy, was observed in 22 of the 25 patients (88%). At the end of therapy, HCV RNA was undetectable in all patients. At 4 and 12 weeks after completing DAA therapy, all had a sustained virological response. The tolerance to anti-HCV therapy was excellent and no adverse event was observed. A significant decrease in calcineurin inhibitor levels was observed after HCV clearance. New-generation oral DAAs are efficient and safe to treat HCV infection after kidney transplantation.

[Epidemiological description of patients with neurological conditions in kidney transplant recipients]. / Epidémiologie des patients neurologiques dans une population de transplantés rénaux.

OBJECTIVES: The aim of this study was to describe the epidemiology of neuropathic bladder in kidney transplant patients. PATIENTS AND METHODS: Patients with terminal chronic kidney disease related to neurogenic bladder were sorted out from a population of 1286 kidney transplant recipients operated between 1993 and 2008. RESULTS: Thirty-three patients, 26 men and seven women, mean age 46.9+/-12.4 years old at the transplantation time were found out. Neurological conditions were spinal dysraphism in 39.4% of the cases, brain injury in 18.2%, cerebrovascular accident in 15.2%, spinal cord injury in 12.2%, myelitis in 6%, congenital encephalopathy in 6% and Hinmann's syndrome in 3%. Mean time between the onset of the neurological disease and the beginning of the dialysis was 21.7+/-11.9 years. CONCLUSION: Prevalence of patients with neuropathic bladder in kidney transplant patients is 2.6%. Most frequent neurological conditions involved are spinal dysraphism and brain injury. The onset of the dialysis occurs 21 years on average after the diagnosis of the neurological disease in patients with mean age of 37.8 years.

Impaired spatial learning and unaltered neurogenesis in a transgenic model of Alzheimer's disease after oral aluminum exposure.

Although it is well established that aluminum (Al) is neurotoxic, the potential role of this element in the etiology of Alzheimer's disease (AD) is not well established. In this study, we evaluated the effects of oral Al exposure on spatial learning, memory and neurogenesis in Tg2576 mice, an animal model of AD in which Abeta plaques start to be deposited at 9 months of age. Aluminum was given as Al lactate (11 mg/g of food) for 6 months. At 11 months of age a water maze test was carried out to evaluate learning and memory. Subsequently, mice were injected with bromo-deoxyuridine (BrdU) and sacrificed 24 hours or 28 days after the last injection in order to assess proliferation, survival and differentiation of neurons. We observed impaired acquisition in the water maze task in Al-treated Tg2576 mice, as well as worse memory in the Al-exposed groups. In terms of neurogenesis, no effects of aluminum were observed in proliferation, survival and differentiation. The results of this investigation suggest that Tg2576 mice fed for 210 days with rodent chow supplemented with Al lactate at 11 mg/g of food have impaired spatial learning although their neurogenesis remains unmodified.

Incidence and predictive factors for infectious disease after rituximab therapy in kidney-transplant patients.

Rituximab off-label use includes organ transplantation. We review the occurrence of infectious disease and its outcome after rituximab therapy. Between April 2004 and August 2008, 77 kidney-transplant patients received rituximab therapy [2-8 courses (median 4) of 375 mg/m2 each] for various reasons. Their results were compared with a control group (n=902) who had received no rituximab. After a median follow-up of 16.5 (1-55) months for rituximab patients and 60.9 (1.25-142.7) months for control patients, the incidence of infectious disease was 45.45% and 53.9% (ns), respectively. The incidence of bacterial infection was similar between the two groups, whereas the viral-infection rate was significantly lower, and the rate of fungal infection was significantly higher in the rituximab group. Nine out of 77 patients (11.68%) died after rituximab therapy, of which seven deaths (9.09%) were related to an infectious disease, compared to 1.55% in the controls (p=0.0007). In the whole population, the independent predictive factors for infection-induced death were the combined use of rituximab and antithymocyte-globulin given for induction or anti-rejection therapy, recipient age, and bacterial and fungal infections. After kidney transplantation, the use of rituximab is associated with a high risk of infectious disease and death related to infectious disease.

Aminothiols and allantoin in chronic dialysis patients: effects of hemodialysis sessions.

BACKGROUND: To investigate the possible relationship between homocysteine and allantoin levels in hemodialyzed patients, serum levels of thiols and purine compounds were analyzed before and after dialysis sessions. METHODS: 16 clinically stable non-diabetic patients hemodialyzed on polysulfone membranes were compared with 36 control subjects. Serum samples were collected before and after hemodialysis sessions. Total homocysteine, cysteine, glutathione, cysteinylglycine, uric acid, hypoxanthine, and allantoin were measured by capillary electrophoresis. RESULTS: Pre-dialysis homocysteine, allantoin, and uric acid were significantly elevated in dialysis patients as compared to controls. Cysteine, glutathione, and hypoxanthine levels were similar in both groups. Homocysteine significantly decreased, but did not normalize after dialysis sessions. Glutathione and cysteinylglycine levels remained unchanged after dialysis sessions, whereas cysteine decreased. Uric acid, hypoxanthine, and allantoin levels were significantly reduced by dialysis sessions. The allantoin/uric acid ratio was higher in dialyzed patients before hemodialysis (0.049 +/- 0.023 vs. 0.016 +/- 0.012 in controls; p < 0.001), and became elevated after a dialysis session (0.084 +/- 0.033; p = 0.002). CONCLUSIONS: Despite the use of biocompatible membranes, homeostasis of thiols and purine compounds is disturbed in hemodialysed patients. We suggest that allantoin could be used as a marker for oxidative stress in hemodialyzed patients.

Effects of oral aluminum exposure on behavior and neurogenesis in a transgenic mouse model of Alzheimer's disease.

The effects of a very low oral dose of Al on spatial learning and neurogenesis were evaluated in a transgenic mouse (Tg 2576) model of Alzheimer disease. At 5 months of age, wild and Tg 2576 mice received a diet supplemented with Al lactate at 0 and 1 mg/g of diet for 120 days. The experimental groups (n=7-8) were: control wild, Al-treated wild, control transgenic, and Al-treated transgenic. After 3 months of Al exposure, activity in an open-field and learning in a water maze were evaluated. At the end of the behavioral testing, in order to study cell proliferation and differentiation in the hippocampus, mice were injected with 5-bromo-2-deoxyuridine (BrdU) and sacrificed 1 or 28 days after the last BrdU injection. Tg 2576 mice were impaired in both acquisition and retention of the water maze task, showing higher amounts of beta-amyloid fragments in brain. Aluminum exposure impaired learning and memory in wild mice and increased the total number of proliferating cells in the dentate gyrus of hippocampus. The low Al doses here experimented suggest that this element might impair cognition in the general population at doses comparable to current levels of human exposure. Although these doses are not enough to interact with the amyloidogenic pathway, an increase in cell proliferation can indicate a reactive response of the brain to Al insult. Further investigations should be performed to corroborate the effects observed at very low doses of Al and to study the potential effects derived from a longer exposure period.

Conversion from sirolimus to everolimus in maintenance renal transplant recipients within a calcineurin inhibitor-free regimen: results of a 6-month pilot study.

AIM: To provide data on conversion of kidney transplant patients from sirolimus to everolimus. MATERIALS AND METHODS: In this 6-month prospective, open-label pilot study, maintenance renal transplant patients receiving sirolimus, mycophenolic acid and corticosteroids without concomitant calcineurin inhibitor (CNI) therapy were converted to everolimus 8 mg/day (8 - 15 ng/ml), and followed for 6 months. Mycophenolic acid and corticosteroid therapy were continued unchanged. Patients with acute rejection within the previous 3 months were excluded. RESULTS: 11 patients were recruited and completed the study (mean 5.1 +/- 1.8 years post transplant). Mean everolimus trough level remained within target throughout the study. Mean GFR remained stable (Day 0, 48.4 +/- 8.4 ml/min/1.73 m2, Month 6, 49.5 +/- 17.3 ml/ min/1.73 m2 (p = 0.966), as did mean renal phosphate threshold (TmPO4/GFR) (Day 0, 0.41 +/- 0.15 mmol/l, Month 6, 0.40 +/- 0.17 mmol/l (p = 0.966)). Serum phosphates increased significantly from 0.71 to 0.77 mmol/l (p = 0.01), but tubular reabsorption of phosphates and 24-h phosphaturia remained unchanged and mean PTH concentration tended to decrease. No patient died, lost their graft or experienced biopsy-proven acute rejection after conversion. There were no cases of CMV infection. Tolerability remained similar post conversion. Hematological and lipid parameters remained stable. Liver enzymes and sex hormones remained within normal ranges. CONCLUSION: This pilot study suggests that converting kidney transplant patients receiving CNI-free maintenance immunosuppression from sirolimus to everolimus, at relatively high exposure levels, is safe and easily manageable. There was no consistent evidence for a change in GFR or proximal tubular function.

Relapse of membranous glomerulopathy after kidney transplantation: sustained remittance induced by rituximab.

Membranous glomerulopathy (MG) is a rare cause of chronic kidney disease. However, after kidney transplantation (KT), despite immunosuppression, it often relapses on the allograft. Herein, we report on a male kidney-transplant patient, aged 27 years, who developed overt nephrotic syndrome 11 months after KT. This was related to relapsing MG, as evidenced by the allograft biopsy, which, in addition, showed CD3 (+) and CD20 (+) interstitial lymphocyte infiltration. The patient was treated with rituximab: 375 mg/m2/week for 4 consecutive weeks, followed by one additional injection every 3 months for one year. Remission was observed before the third rituximab injection. After a follow-up of 42 months, the patient was still in remission, i.e., microalbuminuria of 107 mg/day.

Disseminated herpes simplex type-2 (HSV-2) infection after solid-organ transplantation.

We report on three cases of severe disseminated Herpes simplex type-2 (HSV-2) infection that occurred in two orthotopic liver-transplant (OLT) and one renal-transplant patients. In two cases, i.e., in the OLT patients, this was associated with HSV-2-related acute hepatitis. The rapid onset of IV acyclovir (ACV) therapy led to recovery within 8-12 days. Although rare, HSV-2-disseminated infection, in the context of organ transplantation may be life-threatening, but can be cured if ACV therapy is initiated early in the course of this disease.

Darbepoetin-alfa in renal-transplant patients: an observational monocentric study.

BACKGROUND: Anemia, frequent in post-transplant patients, has been associated with cardiovascular outcomes. Although recombinant human erythropoietin (rHuEPO) is used in post-transplant anemic patients, little information is available concerning the use of darbepoetin-alfa (DA) in this population. METHODS: Eligible patients had been recipients of a kidney graft for > 3 months, had anemia and chronic renal failure, but no iron deficiency. 38 patients, not previously treated by rHuEPO (Group 1), were given DA, and 35 rHuEPO-treated patients (Group 2) were switched to DA according to European Summary of Product Characteristics. Only the subcutaneous route was used. Dose adjustments were done to maintain Hb at 11 - 13 g/dl. Hb levels and DA dosage were assessed at baseline, and at Months 3 and 6. RESULTS: Mean age (A+/- SD) of patients was 47.7 (A+/- 13.4) years (53% male). Mean duration of transplantation was 8.5 (A+/- 5.5) years and mean creatinine clearance was 42.5 (A+/- 19.8) ml/min. In Group 1, mean Hb became increased by +1.27 g/dl (95% CI 0.61, 1.94) and mean DA dose was decreased by 44% between baseline and M6. In Group 2, mean Hb and DA dose remained stable between baseline and M6. Hb response to DA appeared faster in patients who had received a transplant for less than 3 years, and lower in patients who had received a transplant more than 12 years previously. CONCLUSIONS: DA effectively corrected anemia in renal-transplant patients, in previously treated patients and in EPO-naive patients. DA was also found to be well-tolerated.

Recurrence of hemolytic uremic syndrome after renal transplantation.

Non-Shiga toxin-associated hemolytic uremic syndrome (non-Stx-HUS) is a rare disease. The clinical outcome is often unfavorable: 50% of patients progress to end-stage renal failure. Several mutations in complement regulatory genes predispose to non-Stx-HUS. Transplantation outcomes are poor among patients with either mutation in the genes encoding complement H or I factors, with 80% graft loss due to HUS recurrence. In contrast, patients with mutation in the gene encoding MCP have no disease relapse after transplantation. There are no treatment guidelines for non-Stx-HUS recurrence. Herein we have presented 8 patients with non-Stx-HUS recurrence after transplantation during the last 10 years in the South of France. HUS recurrence, which occurred early after transplantation in all but 1 patient, was treated by plasma exchange (PE) with substitution by fresh frozen plasma (FFP). Three patients still treated with long-term plasma therapy have no recurrence at 15, 19, or 24 months. An international registry would help to define new guidelines.

Hepatitis C virus viral load after conversion from tacrolimus to cyclosporine in liver transplant patients: a pilot study.

UNLABELLED: We assessed whether conversion from tacrolimus (TAC) to cyclosporine (CsA) was associated with a reduction in hepatitis C virus (HCV) viral load among HCV-positive liver transplant (OLT) patients. PATIENTS AND METHODS: Nine OLT patients with recurrent HCV have TAC and prednisone immunosuppression. None received any HCV antiviral therapy. After the last intake of TAC, the patients underwent a 12-hour area under the curve (AUC(12)) measurement of both TAC and HCV viral loads. The next morning (D(0)) patients were given CsA (4 mg/kg bid). At the first intake of CsA and at 1 month (M(1)) later, the patients underwent AUC(12) for CsA and HCV viral loads. Biological data, including aspartate (AST) and alanine (ALT) aminotransferase, gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (AP), and bilirubin levels, were collected during AUC(12), and at M(1) and M(3). RESULTS: With respect to liver enzymes (AST, ALT, GGT), there was no significant difference between D(0), M(1), and M(3). Conversely, there was a significant decrease in AP between D(0) and M(3) (P = .02), and a significant increase in total bilirubin between D(0) and M(1) (P = .04), and between D(0) and M(3) (P = .01). HCV viral load significantly increased by M(3) (P = .01). At no time (D(0), M(1)) was there any correlation between the AUC(12) of TAC or CsA, and between AUC(12) HCV viral load. CONCLUSION: This pilot study found no acute or chronic anti-HCV effects from CsA that were evident within 12 hours after CsA administrations or beyond 1 month of CsA therapy, respectively.

An unusual cause of acute renal failure in a kidney transplant recipient: salmonella enteritidis post-infectious glomerulonephritis.

BACKGROUND: Salmonella enteritidis-associated acute renal failure has often been described and is usually a result of dehydration or of rhabdomyolysis. A few cases of acute renal failure with glomerular syndrome, caused by S. enteritidis infection, have been reported in the literature, but none have been proven by histological findings. METHODS: Herein, we report on a case of S. enteritidis-related glomerulonephritis that occurred in a 42-year-old male transplant recipient. He was admitted with fever, signs of urinary infection, diarrhea, and nephritic syndrome, i.e. edema, hypertension, increase in serum creatinine, microscopic hematuria, proteinuria. His urine culture tested positive for S. enteritidis. RESULTS: Under light microscopy, the graft biopsy showed proliferative and exudative endocapillary glomerulonephritis. In addition, there was polymorphonuclear infiltration of the interstitium, and extra-capillary proliferation in one glomerulus. Immunofluorescence showed granular deposits of C3 in the mesangium. Electron microscopy showed electron-dense deposits typical of humps. He fully recovered on a double antibiotic therapy that included ofloxacin and amikacin. CONCLUSION: Although acute renal failure related to non-typhoidal Salmonella infections are often related to dehydration or rhabdomyolysis, this case report shows that it might also be related to immune complex-mediated glomerulonephritis manifesting as nephritic syndrome.

Thrombotic microangiopathy in a sirolimus-treated renal transplant patient receiving gemcitabine for lung cancer.

BACKGROUND: Many etiologies lead to thrombotic microangiopathy (TMA), amongst which are antineoplastic chemotherapies. Gemcitabine, a nucleoside analogue, has been approved for the treatment ofbladder and advanced non-small cell lung carcinomas (NSCLC). The reported incidence of gemcitabine-associated TMA in the literature is low, ranging from 0.015-0.31%. METHODS: Herein, we describe the first reported case of gemcitabine-induced TMA in a renal transplant patient. This occurred in a 54-year-old male transplant recipient undergoing sirolimus-based immunosuppression. In February 2005, he was diagnosed to have NSCLC, for which he received dual chemotherapy, including carboplatin and gemcitabine. After the third cycle he developed TMA. RESULTS: On admission, he presented with weakness, edema, normal blood pressure, leucopenia (2440/mm3), thrombopenia (11,000/mm3), hemolytic anemia with hemoglobin at 8 g/dl, schistocytes between 18-33% per hundred, increase in lactate dehydrogenase at 600 IU/l (N <380), and decreased haptoglobin at 0.29 g/l. Renal function was stable: serum creatinine was 1.3 mg/dl, albuminemia 30 g/l, proteinuria was present at 3 g/l in association with microscopic hematuria, and sirolimus trough level was 6.4 ng/ml. Treatment included infusions of fresh frozen plasma, withdrawal of sirolimus, which was replaced by mycophenolate mofetil, and suspension of chemotherapy. He fully recovered from TMA within 4 weeks. The concomitant use of sirolimus, which inhibits vascular endothelial growth factor, plus gemcitabine may have resulted in TMA.

Prospective evaluation of BK virus DNAemia in renal transplant patients and their transplant outcome.

BACKGROUND: After renal transplantation, the prevalence of BK virus (BKV) viruria, viremia, and nephritis (BKVAN) has been estimated at 30%, 13%, and 8%, respectively. PATIENTS AND METHODS: The aim of this prospective study was to assess the occurrence of BKV DNAemia during the first year after renal transplantation and to determine the prevalence of BKVAN, in the absence of immunosuppression alteration, following positive BKV DNA. BKV DNAemia was assessed systematically in 104 renal transplant patients on postoperative days 60, 90, 135, 180, 270, and 360. RESULTS: Of the 104 patients, 7 (6.7%) presented with at least 1 episode of BKV DNAemia. Those with positive BKV DNAemia had a cumulative steroid dose administered from days 0 to 7 which was higher than those without BKV DNAemia (2.13 +/- 0.6 vs 1.6 +/- 0.4; P = .024). The first BKV DNAemia occurred at 170 (30-460) days posttransplantation. Of the 7 patients who experienced at least 1 BKV DNAemia, 3 had 1 occurrence, but the other 4 had repeated occurrences. These 4 patients developed overt BKVAN at 1 (2 cases) to 2 weeks (2 cases) after the first occurrence of BKV DNAemia. These 4 patients were withdrawn from mycophenolate mofetil, which was in all cases replaced by leflunomide. With a follow-up ranging from 14 to 24 months after the first episode of BKV DNAemia, patient and graft survivals were both 100%. Current serum creatinine ranges from 97 to 173 micro mol/L for those who had only 1 episode of BKV DNAemia, and from 144 to 240 micro mol/L for those who had overt BKVAN. CONCLUSION: Although BKV DNAemia is a rare event after renal transplantation, it is often associated with BKVAN, which may be treated successfully by the alleviation of immunosuppression and leflunomide therapies.