Marie Essig

Inhibitory ITAM Signaling by FcαRI-FcRγ Chain Controls Multiple Activating Responses and Prevents Renal Inflammation

Inhibitory signaling is an emerging function of ITAM-bearing immunoreceptors in the maintenance of homeostasis. Monovalent targeting of the IgA Fc receptor (FcαRI or CD89) by anti-FcαRI Fab triggers potent inhibitory ITAM (ITAMi) signaling through the associated FcRγ chain (FcαRI-FcRγ ITAMi) that prevents IgG phagocytosis and IgE-mediated asthma. It is not known whether FcαRI-FcRγ ITAMi signaling controls receptors that do not function through an ITAM and whether this inhibition requires Src homology protein 1 phosphatase. We show in this study that FcαRI-Fcγ ITAMi signals depend on Src homology protein 1 phosphatase to target multiple non-ITAM-bearing receptors such as chemotactic receptors, cytokine receptors, and TLRs. We found that anti-FcαRI Fab treatment in vivo reduced kidney inflammation in models of immune-mediated glomerulonephritis and nonimmune obstructive nephropathy by a mechanism that involved decreased inflammatory cell infiltration and fibrosis development. This treatment also prevented ex vivo LPS activation of monocytes from patients with lupus nephritis or vasculitis, as well as receptor activation through serum IgA complexes from IgA nephropathy patients. These findings point to a crucial role of FcαRI-FcRγ ITAMi signaling in the control of multiple heterologous or autologous inflammatory responses. They also identify anti-FcαRI Fab as a new potential therapeutic tool for preventing progression of renal inflammatory diseases.

Mast cells and inflammatory kidney disease

Summary:  Inflammatory kidney disease involves a complex network of interactions between resident kidney and infiltrating hematopoietic cells. Mast cells (MCs) are constitutively found in kidneys in small numbers but increase considerably in various renal diseases. While this increase is usually interpreted as a sign of pathological involvement, recent data using MC‐deficient animals show their ability to restore kidney homeostasis. In anti‐glomerular basement membrane antibody‐induced glomerulonephritis, MCs are protective by initiating repair and remodeling functions counteracting the devastating effects of glomerular injury. Protection may also include immunoregulatory capacities to limit autoreactive T‐cell responses. MCs also control tubulointerstitial fibrosis by activating tissue remodeling and neutralizing fibrotic factors. Release of mediators by MCs during inflammation, however, could also promote unwanted responses that ultimately lead to destruction of kidney structure, as exemplified by data showing either protection or aggravation in related renal disease models. Similarly, while the action of proteases may initially be beneficial, the generation of fibrosis‐promoting angiotensin II by chymase also shows the limits of adaptive responses to achieve homeostasis. Thus, it is likely the physiological context involving the interaction with other cells and inflammatory mediators that determines the final action of MCs in the development of kidney disease.

Fcα receptor I activation induces leukocyte recruitment and promotes aggravation of glomerulonephritis through the FcRγ adaptor

Myeloid cells bear Fc receptors (FcR) that mediate inflammatory signaling through the ITAM‐containing FcRγ adaptor. They express FcRγ‐associated FcαRI, which modulate either activating or inhibitory signaling depending on the type of ligand interaction. The role of FcαRIγ in disease progression remains unknown, notably in IgA nephropathy (IgAN), one of major causes of end‐stage renal disease, in which large amounts of circulating IgA‐immune complexes (IC) may mediate receptor activation. To analyze the involvement of FcαRI activation in glomerulonephritis (GN), we generated Tg mice expressing a mutated, signaling‐incompetent, human FcαRIR209L that cannot associate with FcRγ. Like FcαRIwt‐Tg mice, they developed mesangial IgA deposits but not macrophage infiltration. FcαRI activation in FcαRIwt, but not in FcαRIR209L, Tg mice resulted in marked inflammation with severe proteinuria and leukocyte infiltration in spontaneous IgAN or anti‐glomerular basement membrane Ab‐induced GN models. Receptor triggering of syngenically transferred FcαRIwt Tg macrophages into non‐Tg animals induced their recruitment into injured kidneys during GN development. FcαRIwt cross‐linking on macrophages activated MAP kinases and production of TNF‐α and MCP‐1. Moreover, IgA‐IC from IgAN patients activated FcαRI and induced TNF‐α production. Thus, FcαRI activation mediates GN progression by initiating a cytokine/chemokine cascade that promotes leukocyte recruitment and kidney damage.

Clinical characteristics and outcomes of childhood-onset ANCA-associated vasculitis: a French nationwide study

BACKGROUND Data on anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis are scarce in children. The current study is aimed at describing the clinical features and outcomes of childhood-onset ANCA-associated vasculitis (AAV). METHODS We conducted a retrospective French multicentre study involving patients in whom AAV was diagnosed before the age of 18 years. Inclusion criteria were (i) granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) according to classification criteria of the European League Against Rheumatism/Paediatric Rheumatology European Society, and (ii) ANCA positivity. Patient and renal survival were analysed. RESULTS Among 66 children included, 80% were female, 42% had GPA and 58% MPA including renal-limited vasculitis, 67% were pANCA+ and 33% cANCA+. The mean incidence of reported cases increased to 0.45 per million children/year in the period 2006-10. Median age at diagnosis was 11.5 years, and median time to diagnosis was 1 month. Initial symptoms included fever and fatigue (79%), skin lesions (41%), arthritis (42%), pulmonary (45%) and renal involvement (88%). Clinical features were similar between GPA and MPA with the exception of upper airway impairment (28%) specific of GPA. Ninety percent of the patients achieved remission after induction treatment. After a median follow-up of 5.2 years, 4 patients (6%) died, corresponding to a mortality rate of 1.2 per 100 person-years, and 22 patients (34%) developed end-stage renal disease (ESRD). Renal survival was 74, 70 and 59% at 1, 5 and 10 years, respectively. In a multivariable Cox regression model, baseline glomerular filtration rate, ethnic origin, histopathological classification and era of treatment were associated with the occurrence of ESRD. Relapse-free survival was 57% at 5 years and 34% at 10 years of follow-up. Patient and renal outcome did not significantly differ between GPA and MPA. CONCLUSION Childhood-onset AAV is a rare disease characterized by female predominance, delayed diagnosis, frequent renal impairment and a high remission rate. Baseline GFR and new histopathological classification system are strong predictors of ESRD. Renal survival in childhood AAV has improved over time.

Establishing Biomarkers in Transplant Medicine: A Critical Review of Current Approaches

Although the management of kidney transplant recipients has greatly improved over recent decades, the assessment of individual risks remains highly imperfect. Individualized strategies are necessary to recognize and prevent immune complications early and to fine-tune immunosuppression, with the overall goal to improve patient and graft outcomes. This review discusses current biomarkers and their limitations, and recent advancements in the field of noninvasive biomarker discovery. A wealth of noninvasive monitoring tools has been suggested that use easily accessible biological fluids such as urine and blood, allowing frequent and sequential assessments of recipients immune status. This includes functional cell-based assays and the evaluation of molecular expression on a wide spectrum of platforms. Nevertheless, the translation and validation of exploratory findings and their implementation into standard clinical practice remain challenging. This requires dedicated prospective interventional trials demonstrating that the use of these biomarkers avoids invasive procedures and improves patient or transplant outcomes.

Light chain deposition disease without glomerular proteinuria: a diagnostic challenge for the nephrologist

BACKGROUND Renal involvement in light chain (LC) deposition disease (LCDD) is typically characterized by nodular glomerulosclerosis and nephrotic range proteinuria. Rare cases of LCDD without glomerular symptoms have been reported, but clinical and pathological characteristics of this entity remain poorly described. METHODS This multi-centre retrospective study included 14 patients with biopsy-proven renal LCDD and proteinuria <0.5 g/day at diagnosis. RESULTS Baseline median serum creatinine was 281 (136-594) μmol/L, with a glomerular filtration rate of 20 (6-48) mL/min/1.73 m(2). A serum monoclonal immunoglobulin was detected in 12 cases and LC proteinuria only in 7, always of kappa isotype. Monoclonal gammopathy of undetermined significance/indolent multiple myeloma (MM) was diagnosed in nine cases, symptomatic MM in three cases. Hypertension was almost constant (10 of 14). Immunofluorescence studies of kidney biopsies showed linear kappa LC deposition along tubular basement membranes in all cases, with linear glomerular and vascular LC deposits in 11 and 10 patients, respectively. By light microscopy, tubulo-interstitial lesions were prominent in all patients and focal nodular glomerulosclerosis was only observed in two cases. Identification of LCDD led to initiation of chemotherapy in 12 cases. After a median follow-up of 25.5 months, five patients died and four progressed to end-stage renal disease. Renal response occurred in five of the eight patients who achieved sustained haematological response. CONCLUSIONS LCDD can cause severe renal dysfunction, despite the absence of glomerular symptoms. Early identification of the disease and introduction of a chemotherapy targeting the underlying plasma cell disorder may preserve long-term renal prognosis.

CKD and Its Risk Factors among Patients with Cystinuria

BACKGROUND AND OBJECTIVES Cystinuria is an autosomal recessive disorder affecting renal cystine reabsorption; it causes 1% and 8% of stones in adults and children, respectively. This study aimed to determine epidemiologic and clinical characteristics as well as comorbidities among cystinuric patients, focusing on CKD and high BP. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This retrospective study was conducted in France, and involved 47 adult and pediatric nephrology and urology centers from April 2010 to January 2012. Data were collected from 442 cystinuric patients. RESULTS Median age at onset of symptoms was 16.7 (minimum to maximum, 0.3-72.1) years and median diagnosis delay was 1.3 (0-45.7) years. Urinary alkalinization and cystine-binding thiol were prescribed for 88.8% and 52.2% of patients, respectively, and 81.8% had at least one urological procedure. Five patients (1.1%, n=4 men) had to be treated by dialysis at a median age of 35.0 years (11.8-70.7). Among the 314 patients aged ≥16 years, using the last available plasma creatinine, 22.5% had an eGFR≥90 ml/min per 1.73 m(2) (calculated by the Modification of Diet in Renal Disease equation), whereas 50.6%, 15.6%, 7.6%, 2.9%, and 0.6% had an eGFR of 60-89, 45-59, 30-44, 15-29, and <15, respectively. Among these 314 patients, 28.6% had high BP. In multivariate analysis, CKD was associated with age (odds ratio, 1.05 [95% confidence interval, 1.03 to 1.07]; P<0.001), hypertension (3.30 [1.54 to 7.10]; P=0.002), and severe damage of renal parenchyma defined as a past history of partial or total nephrectomy, a solitary congenital kidney, or at least one kidney with a size <10 cm in patients aged ≥16 years (4.39 [2.00 to 9.62]; P<0.001), whereas hypertension was associated with age (1.06 [1.04 to 1.08]; P<0.001), male sex (2.3 [1.3 to 4.1]; P=0.003), and an eGFR<60 ml/min per 1.73 m(2) (2.7 [1.5 to 5.1]; P=0.001). CONCLUSIONS CKD and high BP occur frequently in patients with cystinuria and should be routinely screened.

Anti-hepatitis C virus drugs and kidney

Hepatitis C virus (HCV) mainly targets the liver but can also induce extrahepatic manifestations. The kidney may be impacted via an immune mediated mechanism or a cytopathic effect. HCV patients are clearly at a greater risk of chronic kidney disease (CKD) than uninfected patients are, and the presence of CKD increases mortality. Interferon-based therapies and ribavirin are difficult to manage and are poorly effective in end-stage renal disease and hemodialysis. These patients should be given priority treatment with new direct anti-viral agents (DAAs) while avoiding peginterferon and ribavirin. The first results were convincing. To aid in the correct use of these drugs in patients with renal insufficiency, their pharmacokinetic properties and potential renal toxicity must be known. The renal toxicity of these new drugs was not a safety signal in clinical trials, and the drugs are generally efficient in these frail populations. These drugs are usually well tolerated, but recent cohort studies have demonstrated that these new regimens may be associated with renal side effects, especially when using sofosbuvir combinations. HCV, renal diseases and comorbidities are intimately linked. The close monitoring of renal function is required, particularly for at-risk patients (transplanted, HIV-coinfected, CKD, hypertensive or diabetic patients). New DAA regimens, which will soon be approved, will probably change the landscape.

Evolution and Determinants of Health-Related Quality-of-Life in Kidney Transplant Patients Over the First 3 Years After Transplantation.

Background Health-related quality of life (HRQOL) usually improved after kidney transplantation; however, a non-negligible number of patients did not benefit from transplantation in HRQOL. The aims of this cohort study were to describe the evolution of HRQOL in kidney transplant recipients to search for subgroups with distinct time profiles and to investigate these determinants. Methods Three hundred thirty-seven adult patients were followed up from 1 to 36 months after kidney transplantation. Each patient completed repeated HRQOL assessments (median, 5; range, 2-9). K-means for longitudinal data was used to identify homogeneous clusters of HRQOL time profiles obtained for the mental and physical composite scores (MCS and PCS) and for the 8 dimensions of the short-form 36 scale. Covariates associated with these clusters were investigated using random forest analysis. Magnitude and shape of the HRQOL variations over time were investigated using linear regression mixed models. Results Two longitudinal clusters were identified for the time profiles of PCS and MCS. Patients classified in the higher cluster (ie, 60% of the population) exhibited a steady-state HRQOL, similar on average to the general population, whereas in the lower cluster, PCS and MCS scores were significantly lower than in the general population. Muscular weakness in the first year after transplantation explained 19% of the interpatient variability of PCS 3 months after transplantation, whereas associated with anxiety, it explained 24% of interpatient MCS variability. Conclusions This work suggests to promote (i) physical rehabilitation programs after transplantation to curb the muscular loss and (ii) systematic attention to the patients anxiety.

Minimization of maintenance immunosuppressive therapy after renal transplantation comparing cyclosporine A/azathioprine or cyclosporine A/mycophenolate mofetil bitherapy to cyclosporine A monotherapy: a 10‐year postrandomization follow‐up study

Long‐term outcomes in renal transplant recipients withdrawn from steroid and submitted to further minimization of immunosuppressive regimen after 1 year are lacking. In this multicenter study, 204 low immunological risk kidney transplant recipients were randomized 14.2 ± 3.7 months post‐transplantation to receive either cyclosporine A (CsA) + azathioprine (AZA; n = 53), CsA + mycophenolate mofetil (MMF; n = 53), or CsA monotherapy (n = 98). At 3 years postrandomization, the occurrence of biopsy for graft dysfunction was similar in bitherapy and monotherapy groups (21/106 vs. 26/98; P = 0.25). At 10 years postrandomization, patients’ survival was 100%, 94.2%, and 95.8% (P = 0.25), and death‐censored graft survival was 94.9%, 94.7%, and 95.2% (P = 0.34) in AZA, MMF, and CsA groups, respectively. Mean estimated glomerular filtration rate was 70.4 ± 31.1, 60.1 ± 22.2, and 60.1 ± 19.0 ml/min/1.73 m2, respectively (P = 0.16). The incidence of biopsy‐proven acute rejection was 1.4%/year in the whole cohort. None of the patients developed polyomavirus‐associated nephropathy. The main cause of graft loss (n = 12) was chronic antibody‐mediated rejection (n = 6). De novo donor‐specific antibodies were detected in 13% of AZA‐, 21% of MMF‐, and 14% of CsA‐treated patients (P = 0.29). CsA monotherapy after 1 year is safe and associated with prolonged graft survival in well‐selected renal transplant recipient (ClinicalTrials.gov number: 980654).