Beyond the First Year: Epidemiology and Management of Late-Onset Opportunistic Infections After Kidney Transplantation.

Late opportunistic infections (OI) occurring beyond the first year after kidney transplantation (KT) are poorly described and not targeted by prophylactic strategies. We performed a ten-year retrospective monocentric cohort study describing epidemiology, risk factors and impact of late OI occurring 1 year after KT. We included clinically symptomatic OI requiring treatment besides BK virus nephropathy. Control groups included early OI occurring in the first year after KT, and KT recipients without OI since KT and alive with a functional allograft at 1 year. Among 1066 KT recipients, 185 (19.4%) presented a first episode of OI 21.0 (8.0-45.0) months after KT: 120 late OI (64.9%) and 65 early OI (35.1%). Late OI were mainly viral (N = 83, 69.2%), mostly herpes zoster (HZ) (N = 36, 43.4%). Pneumocystis represented most late fungal infections (N = 12/25, 48%). Compared to early OI, we reported more pneumocystis (p = 0.002) and less invasive aspergillosis (p = 0.01) among late OI. Patients with late OI were significatively younger at KT (54.0 ± 13.3 vs. 60.2 ± 14.3 years, p = 0.05). Patient and allograft survival rates between late OI and control groups were similar. Only age was independently associated with mortality. While late OI were not associated with higher mortality or graft loss, implementing prophylactic strategies might prevent such infections.

Functional immune assay using interferon-gamma could predict infectious events in end-stage kidney disease.

BACKGROUND: Infections remain the second most common cause of death in patients with end-stage kidney disease (ESKD). We aimed to evaluate non-specific cell-mediated immunity in an ESKD cohort using a functional assay applicable to routine use, QuantiFERON-Monitor (Qiagen), and assess whether it can predict infectious events. METHODS: In this prospective study, we performed the QuantiFERON-Monitor test in 80 subjects including 54 patients with ESKD. QuantiFERON-Monitor is based on the measurement of plasma interferon-gamma (IFN-γ) after stimulation of NK-cells with a TLR-7 agonist, and T-cells with a TCR agonist. Patients were subsequently followed for 6 to 12 months. RESULTS: QuantiFERON-Monitor showed lower stimulated IFN-γ production in ESKD patients (n = 54) compared to healthy donors (n = 19) (p < 0.0001) and to chronic kidney disease stage 3-4 patients (n = 7) (hemodialysis (n = 30): p < 0.01; peritoneal dialysis (n = 13): p = 0.03 and ESKD on conservative management (n = 11): p < 0.001). No significant difference in stimulated IFN-γ production was observed between ESKD patients with renal replacement therapies or conservative management. Stimulated IFN-γ production was significantly lower in patients later developing infections (13.9 [5.5-48.3] IU/mL vs 85.8 [35.5-236] IU/mL, p = 0.007). Using ROC analysis, we identified a cutoff value of 63.55 IU/mL (sensitivity = 80.95%, specificity = 79.17%, AUC = 0.78, p = 0.008) to discriminate patients at higher risk of infections. Patients with stimulated IFN-γ levels measured by QuantiFERON Monitor below 63.55 IU/mL (n = 21) had a hazard ratio of 10.71 ([3.68-31.13], p < 0.0001) for the development of subsequent infections. CONCLUSION: Monitoring of IFN-γ production after stimulation of innate and adaptive immunity may identify ESKD patients with high risk of infection. This allows for therapeutic interventions to restore cellular immunity, thereby minimizing both infections and rejections after kidney-transplantation.

Safety of sofosbuvir-based regimens after liver transplantation: longitudinal assessment of renal function in the prospective ANRS CO23 CUPILT study.

BACKGROUND: In liver transplant recipients with hepatitis C virus recurrence, there is concern about renal safety of sofosbuvir-based regimens. Changes in serum creatinine or in the estimated glomerular filtration rate (eGFR) under treatment are used to look for possible renal toxicity. However, serum creatinine and eGFR are highly variable. AIM: To analyse renal function trajectory with numerous assays of serum creatinine over a long period of time. METHODS: In a multicentre cohort of 139 patients, the eGFR was obtained from serum creatinine using the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation. Slopes of eGFR were defined as a change in eGFR during a period divided by time. Pre-treatment, on-treatment and post-treatment periods were 9 months, 3-9 months and 4.5 months. Interactions between eGFR slopes and the pre-treatment eGFR, use of ribavirin or mycophenolate mofetil, and stage of fibrosis were addressed. On-treatment eGFR slopes were separated in tertiles. Pre- and post-treatment eGFR slopes were compared globally and according to tertiles. RESULTS: The post-treatment eGFR slope was significantly better than pre-treatment eGFR slope (+0.18 (IQR -0.76 to +1.32) vs -0.11 (IQR -1.01 to +0.73) mL/min/1.73 m2 /month, P = 0.03) independently of the pre-treatment eGFR (P = 0.99), ribavirin administration (P = 0.26), mycophenolate mofetil administration (P = 0.51) and stage of fibrosis (F3 and F4 vs lower stages, P = 0.18; F4 vs lower stages, P = 0.08; F4 Child-Pugh B and C vs lower stages, P = 0.38). Tertiles of on-treatment eGFR slopes were -1.71 (IQR -2.54 to -1.48), -0.78 (IQR -1.03 to -0.36) and +0.75 (IQR +0.28 to +1.47) mL/min/1.73 m2 /month. Pre- and post-treatment eGFR slopes were not significantly different according to tertiles (respectively, P = 0.34, 0.08, 0.73). CONCLUSION: The eGFR varies during treatment and gives a confusing picture of the renal safety of sofosbuvir-based regimens. In contrast, longitudinal assessment of the eGFR shows a rising trajectory over longer time, meaning that these therapies are safe for the kidneys in our cohort of liver transplant recipients.

Increased time exposure to tenofovir is associated with a greater decrease in estimated glomerular filtration rate in HIV patients with kidney function of less than 60 ml/min/1.73 m2.

Tenofovir (TDF), atazanovir (ATAZ) and indinavir (IND) have been reported as possible risk factors for incident chronic kidney disease (CKD) in HIV-infected patients. We investigated the relationship between the duration of antiretroviral exposure and estimated glomerular filtration rate (eGFR) evolution in CKD patients. In a cohort of 1,750 HIV-infected patients, we identified 121 CKD patients with a mean follow-up of 44 ± 35 months. The relationship between mean eGFR at baseline, eGFR slope and time exposure to antiretroviral treatment as well as confounding factors were investigated using a joint modeling procedure. Seventy (58%), 30 (25%) and 33 patients (27%), with a mean age of 50.3 ± 11.7 years, mean eGFR at baseline of 53.0 ± 0.8 (ml/min/1.73 m(2)) and eGFR slope of 0.46 ± 0.07 ml/min/1.73 m(2)/year, were exposed to TDF, ATAZ and IND, respectively. In univariate analysis, hepatitis C virus infection, decreased nadir of log CD4 count, high blood pressure at baseline, angiotensin-converting enzyme inhibitor treatment and greater time exposure to TDF during follow-up were associated with a higher slope, whereas greater time exposure to IND was associated with a lower slope. In multivariate analysis, higher TDF time exposure was still significantly associated with eGFR decline, with a dose-effect relationship (slope ± standard error of the mean: 1.1 ± 0.1, 0.5 ± 0.1, -0.07 ± 0.08 and -0.87 ± 0.06 ml/min/1.73 m(2)/year for no time exposure, <34, 34-67 and ≥67%, respectively; trend test: p < 0.001), whereas the IND time exposure association was abolished. In HIV patients with CKD, a greater TDF time exposure was independently associated, in a graded manner, with a greater eGFR decline.

Difference in antigenic determinant profiles between human and rat myeloperoxidase.

We tested whether rat and human MPO have similar antigenic determinants using 36 human MPO-ANCA positive sera, one mouse anti-rat MPO and four mouse anti-human MPO monoclonal reagents. Purified rat and human MPO were used in ELISA, with or without crossinhibition by preincubation with human MPO or irrelevant antigen in the liquid phase. Only one human MPO ANCA positive serum exhibited significant binding in rat MPO ELISA. This binding was poorly inhibited by preincubation with human MPO in the liquid phase, but was conserved after adsorption of non specific anti-rat activity in a chromatography column. Three mouse anti-human MPO IgG monoclonal antibodies did not recognize rat MPO. Only one mouse anti-human MPO IgA monoclonal antibody bound to rat MPO. This binding was poorly inhibited by preincubation with human MPO (35% at 2 micro g/ml). Conversely, the mouse anti-rat MPO monoclonal did not bind human MPO. We have concluded that: (1) Most human MPO-ANCA recognize antigenic determinants on human MPO which are absent on rat MPO. Therefore, human auto-antibodies bind to epitopes which recently appeared after species evolution; (2) Inversely, the mouse anti-rat MPO monoclonal do not bind human MPO. Therefore, rat MPO epitopes have been altered during species evolution; (3) Mice injected with human MPO preferentially develop antibodies against xeno-epitopes which are not present in rodents. Therefore, human MPO may not be the best antigen to raise ANCA in animal models and (4) A comparison of the amino acid sequences of rat and human MPO may help elucidate the major antigenic epitopes.

[Abdominal complications in peritoneal dialysis]. / Les complications abdominales en dialyse péritonéale.

We conducted a 4-year retrospective study (1996-1999) in order to assess the abdominal events in patients on peritoneal dialysis (PD), as well as the technique failure and the death incidence. We enrolled 127 patients in two french dialysis centers, who presented 9 enteric bacterial peritonitis (13.2% of the total peritonitis episodes), occurring 7.6 +/- 7.9 months after PD treatment. Surgery (8 patients) and definitive technique failure (7 patients) were necessary. Hernias were the most frequent with 32.6% of the total abdominal complications. They were either umbilical (7 patients), or inguinal (5 patients) or hiatal (3 patients). Six patients continued on PD without disruption whereas 6 patients had a transient stop and thereafter returned to PD. The other abdominal complications such as gastric and duodenal ulcus (5 patients), oesophagogastric reflux (5 patients), liver diseases (9 patients) occurred during PD treatment without any relationship with the treatment modality. In the diabetic population, abdominal complications were not more frequent but they took place more quickly than in the non diabetic population (5.5 +/- 3.8 months versus 12.9 +/- 16.3 months with p < 0.01). A rapid diagnosis, especially in case of enteric peritonitis, is mandatory to avoid "abdominal catastrophes" mainly due to visceral injury. The incidence of hernia could be decreased if a good clinical approach is effective before PD treatment.

Photopheresis affects the course of experimental allergic encephalomyelitis in Lewis rat.

BACKGROUND/PURPOSE: The mechanism responsible for the beneficial effects of extracorporeal photochemotherapy (ECP) remains unknown. In the rat model of experimental allergic encephalomyelitis (EAE), the transfer of encephalitogenic cells (EAE cells) induces transient passive EAE, followed by resistance to subsequent disease induction through immunization with central nervous system antigens (active EAE). METHODS: We tested whether ECP exerts its therapeutic effect by inducing an immune response targeted on circulating pathogenic T-lymphocytes, which results from their increased immunogenicity. We compared the potential of untreated versus ECP-treated encephalitogenic cells to transfer passive EAE and protect against active induction of the disease. The UVA irradiation conditions were derived from intensive ECP protocols used in human clinical studies. RESULTS: Animals receiving untreated cells showed clinical symptoms following cell transfer but not after subsequent immunisation, whereas those receiving ECP-treated cells remained healthy following cell transfer but experienced clinical symptoms after subsequent immunisation. However, these symptoms were less marked than in control naive rats. CONCLUSION: Under these ECP protocol conditions, ECP-treated cells have no greater active stimulatory potential for the recipient immune system than untreated cells, since they are less effective at triggering the response that causes the resistant state to active EAE. We suggest that intensive ECP protocol may have deleterious effects with a risk of relapses after treatment discontinuation. The search for the irradiation threshold that would inhibit the T-cell pathogenic properties, but retain their ability to educate the immune system, remains a major research challenge.

Extracorporeal photochemotherapy for secondary chronic progressive multiple sclerosis: a pilot study.

BACKGROUND/PURPOSE: Extracorporeal photochemotherapy (ECP) has been proposed for the treatment of various auto- and allo-immune reactions. However, a standard ECP regimen did not significantly alter the course of chronic progressive multiple sclerosis (MS). We tested whether an intensive ECP treatment can affect the course of secondary chronic progressive form of MS. METHODS: Five patients free of immunosuppression were included. Soluble 8-MOP was added ex vivo to a mononuclear cell suspension obtained in a cell separator. This cellular suspension was then irradiated using an UVA irradiator and re-infused into the patient. ECP was performed once a week for 6 weeks and then, depending on clinical evaluation, for a maximum of 6 months, with 2-year follow-up after treatment discontinuation. Scoring was performed with the Kurzke scale and EDSS by a single independent neurologist. RESULTS: One patient was excluded because of recurrent attacks at the very beginning of treatment. Four patients completed the study: one exhibited clinical improvement and three remained stable during the first 6 months of treatment. However, all experienced relapse or worsening of the disease after discontinuation of ECP treatment. CONCLUSION: Our intensive ECP treatment only transiently alters the course of the severe secondary chronic progressive form of MS, with rebound after treatment discontinuation.

[Treatment of vasculitis with antineutrophil cytoplasmic autoantibodies (ACPN)]. / Vascularites avec anticorps anti-cytoplasme des polynucléaires neutrophiles (ACPN).

DIAGNOSIS OF RENAL INVOLVEMENT: The diagnosis of renal involvement in patients with Wegener's disease and microscopic polyangeitis is facilitated with the search for antineutrophil cytoplasmic autoantibodies (ANCA) but still requires biopsy for confirmation. TWO THERAPEUTIC PHASES: Induction should be initiated immediately, and generally leads to initial remission. Long-term treatment is then needed to reduce the risk of recurrence and relapse. FOLLOW-UP: Close monitoring of ANCA levels is important in these patients. Several protocols are currently under evaluation with the aim of limiting immunosuppression toxicity.

[Treatment of vasculitis without antineutrophil cytoplasmic autoantibodies]. / Vascularites sans anticorps anti-cytoplasme des polynucléaires neutrophiles.

UNLABELLED: RENAL INVOLVEMENT: Several types of vascularides without antineutrophil cytoplasmic autoantibodies (ANCA) can affect the kidney. The most frequently encountered are small-vessel vascularides leading to glomerulonephritis: Goodpasture's disease, lupus, and, most importantly, rheumatoid purpura and type II mixed cryoglobulinemia secondary to hepatitis C. Medium-sized vessel vascularitis, such as occurs in polyarthritis nodosa, is exceptional and leads to renal ischemia. Renal involvement in large-vessel vascularities is also exceptional, e.g. temporal artery arteritis and Takayasu's syndrome. THERAPY: Treatment must be adapted to the type of vascularides and also its class (small, medium, or large-vessel disease) and depends on the gravity of each individual patient's situation. A large range of treatments have been proposed, but there is little solid evidence concerning efficacy.

Analysis of anti-neutrophil cytoplasmic antibodies (ANCA): frequency and specificity in a sample of 191 homozygous (PiZZ) alpha1-antitrypsin-deficient subjects.

BACKGROUND: ANCA are autoantibodies directed against polymorphonuclear cell antigens, mainly proteinase 3 (PR3) and myeloperoxidase (MPO), which are implicated in the pathogenesis of small-vessel necrotizing vasculitis. Alpha1-antitrypsin is the main inhibitor of neutral serine proteinase [i.e. human leukocyte elastase (HLE) and PR3] present in PMN alpha-granules (alphaGr). An association first reported by us between PR3 ANCA and the deficient PiZZ phenotype in ANCA-positive systemic vasculitis, now widely confirmed by others, led us to study the incidence and specificity of ANCA among PiZZ subjects. METHODS: We tested a population of 191 PiZZ (273 sera) for ANCA activity versus 272 PiMM matched control subjects using alphaGr or antigen-specific ELISA [PR3, HLE, MPO, lactoferin (LF) and bactericidal/ permeability increasing protein (BPI)]. RESULTS: The incidence of antibodies directed against alphaGr and HLE but not PR3, MPO, LF or BPI was increased in the PiZZ as compared to the PiMM group (Fisher probability respectively P < 0.0001 and P < 0.05). CONCLUSIONS: ANCA not directed against classical antigens (MPO and PR3) may be found in PiZZ patients. However, these patients do not develop systemic vasculitis features. Therefore, alpha1-antitrypsin deficiency is not sufficient to induce ANCA positive vasculitides, and may only act as a second hit amplifying factor.

Alpha1-antitrypsin phenotypes and anti-neutrophil cytoplasmic auto-antibodies in inflammatory bowel disease.

OBJECTIVES: Alpha1-antitrypsin (alpha1-AT) is encoded by a highly polymorphic gene with over 75 codominantly expressed alleles at the protease inhibitor (Pi) locus classified as normal, deficient, dysfunctional or null. The aim of this study was to determine in patients with inflammatory bowel disease: (i) the prevalence of anti-neutrophil cytoplasmic auto-antibodies (ANCA) and their antigen specificities; (ii) alpha1-AT Pi phenotypes; and (iii) possible associations between ANCA, disease activity and deficient alpha1-AT alleles. DESIGN: Study of 95 consecutive patients with ulcerative colitis (UC) and 63 patients with Crohn's disease (CD). METHODS: Diagnosis and disease activity were determined by clinical, endoscopic and histological criteria. ANCA by indirect immunofluorescence (IIF) and Pi phenotyping by isoelectric focusing were performed for all patients. Positive IIF sera were tested in antigen-specific enzyme-linked immunosorbent assay: proteinase 3 (PR3), myeloperoxidase (MPO), lactoferrin (LF), lysozyme, human leucocyte elastase (HLE), cathepsin G and bactericidal/permeability increasing protein (BPI). RESULTS: Sixty-one patients with UC (64.2%) and only 11 with CD (17.5%) had ANCA (P < 0.001). Antigen specificities were PR3 (7/61), MPO (3/61), LF (6/61), HLE (1/63) and BPI (10/61) in UC, and PR3 (2/11) and BPI (2/11) in CD. Three PiZ alleles were found, matching the prevalence in the normal French control population. No relationship was found between the presence of ANCA, antibody specificity, disease activity and deficient alpha1-AT alleles. CONCLUSION: ANCA are more frequent in UC than CD and do not correlate with disease activity. ANCA and protease/antiprotease imbalance do not appear to modulate the clinical course of inflammatory bowel disease.

Effect of protein A immunoadsorption in nephrotic syndrome of various etiologies.

Protein A immunoadsorption (IA) has proved effective in reducing proteinuria in patients with nephrotic syndrome after recurrence of focal and segmental glomerulosclerosis (FSGS) in kidney transplants. The effect of IA in nephrotic syndrome of other etiologies remains unknown. Nine patients with nephrotic syndrome secondary to membranous nephropathy (four cases), diabetes mellitus (one case), IgA nephropathy (two cases), and amyloidosis (two cases) had three to five IA of 2.5 plasma volumes over 4 to 8 d. Patients received no concomitant immunosuppressive treatment, and antihypertensive drugs were left unchanged. Proteinuria decreased from 12.64 +/- 5.49 to 3.35 +/- 2.2 g/24 h (mean +/- SD) in all patients after three to five IA. Hematocrit decreased from 37.32 to 32.64% (12.5% hemodilution) and serum albumin from 25.43 to 18.6 g/L (26.4% decrease). Proteinuria returned to baseline levels within 1 mo, as described in recurrent FSGS following transplantation. When serum albumin balance was controlled by albumin infusion after IA in two patients, comparable decreases in proteinuria were observed. Therefore, IA is effective in producing short-term reduction of proteinuria in nephrotic syndromes related not only to FSGS but also to membranous and IgA nephropathies, diabetes mellitus, and amyloidosis, which suggests that IA removes a nonspecific circulating hemodynamic-altering or permeability-increasing factor.

International Consensus Statement on Testing and Reporting of Antineutrophil Cytoplasmic Antibodies (ANCA)

Antineutrophil cytoplasmic antibody (ANCA) tests are used to diagnose and monitor inflammatory activity in the primary systemic small vessel vasculitides. ANCA is best demonstrated in these diseases by using a combination of indirect immunofluorescence (IIF) of normal peripheral blood neutrophils and enzyme-linked immunosorbent assays (ELISAs) that detect ANCA specific for proteinase 3 (PR3) or myeloperoxidase (MPO). For ANCA testing in "new" patients, IIF must be performed on all serum samples. Serum samples containing ANCA, any other cytoplasmic fluorescence, or an antinuclear antibody (ANA) that results in homogeneous or peripheral nuclear fluorescence then should be tested in ELISAs for PR3-ANCA and MPO-ANCA. Optimally, ELISAs for PR3-ANCA and MPO-ANCA should be performed on all serum samples. Inclusion of the most recent positive sample in the IIF or ELISA may help demonstrate a change in antibody level. Reports should use recommended terms. Any report of positive neutrophil fluorescence issued before the ELISA results are available should indicate that positive fluorescence alone is not specific for the diagnosis of Wegener granulomatosis or microscopic polyangiitis and that decisions about treatment should not be based solely on the ANCA results.

Antineutrophil cytoplasmic antibodies (ANCA) in chronic graft-versus-host disease after allogeneic bone marrow transplantation.

We studied the usefulness of monitoring antineutrophil cytoplasmic antibodies (ANCA) in chronic graft-versus-host disease (cGVHD), a major complication of allogeneic bone marrow transplantation. Antigen-specific ELISA and indirect immunofluorescence (IIF) were used to search for ANCA in 47 allogeneic bone marrow graft recipients who developed cGVHD and in 43 who did not (controls). Eight patients exhibited ANCA IIF positivity in the cGVHD group, but none in the controls. Specificity was confirmed in antigen-specific assays in only two cGVHD patients, both showing antilactoferrin (anti-LF) activity. One of these patients was followed-up, and the antilactoferrin antibodies were found only at the time of active but limited cGVHD. Among three ANCA IIF-positive patients, two had antinuclear autoantibodies and three antineutrophil alloantibodies secondary to blood transfusion, which may have been responsible for false ANCA IIF positivity. It is concluded that ANCA determination is not useful in patients with cGVHD. Polyclonal activation of B lymphocytes could result in ANCA activity during cGVHD. False-positive ANCA could be due to allo-immunization following blood transfusion. Rare patients may present antilactoferrin antibodies of unknown clinical significance.