RESUMEN
BACKGROUND: Globally, the predominant histopathologic characteristic of childhood nephrotic syndrome has been minimal change nephropathy (MCN). However, some studies from Africa and Nigeria have revealed otherwise. It is imperative that this pattern is re-examined from time to time given changing disease and environmental dynamics from place to place. OBJECTIVE: This study aimed to determine the histopathological characteristics of childhood nephrotic syndrome in Ilorin, northcentral Nigeria. METHODS: A prospective study of all new patients aged 2-14 years who presented with clinical features of nephrotic syndrome between January 2010 to December 2023 at the University of Ilorin Teaching Hospital, Ilorin was carried out. All eligible patients underwent renal biopsy. RESULTS: A total of 47 children with nephrotic syndrome were biopsied comprising of 21 males and 26 females making an M: F ratio of 1:1.2. The age range of subjects was 2-14 years with a mean of 7.8 ±3.6 years. The most common histological type of nephrotic syndrome was minimal change nephrotic syndrome (MCNS) which occurred in 35(74.5%) children followed by membranoproliferative glomerulonephritis (MPGN) in 5(10.6%) and focal segmental glomerulosclerosis (FSGS) in 2(4.3%). Of the 35 MCNS patients, 31(88.6%) were steroid sensitive while 4(11.4%) were steroid resistant. CONCLUSION: The predominant histopathological characteristic of childhood nephrotic syndrome was minimal change nephrotic syndrome, which was mostly steroid-sensitive.
CONTEXTE: Au niveau mondial, la principale caractéristique histopathologique du syndrome néphrotique de l'enfant a été la néphropathie à lésions minimales (NLM). Cependant, certaines études en Afrique et au Nigeria ont montré des résultats différents. Il est essentiel de réévaluer ce modèle régulièrement en raison de l'évolution des maladies et de l'environnement d'un endroit à l'autre. OBJECTIF: Cette étude visait à déterminer les caractéristiques histopathologiques du syndrome néphrotique de l'enfant à Ilorin, dans le nord-centre du Nigeria. MÉTHODES: Une étude prospective de tous les nouveaux patients âgés de 2 à 14 ans présentant des signes cliniques de syndrome néphrotique entre janvier 2010 et décembre 2023 à l'hôpital universitaire d'Ilorin, à Ilorin, a été réalisée. Tous les patients éligibles ont subi une biopsie rénale. RÉSULTATS: Au total, 47 enfants atteints du syndrome néphrotique ont été biopsiés, dont 21 garçons et 26 filles, soit un ratio H/F de 1/1,2. La tranche d'âge des sujets était de 2 à 14 ans avec une moyenne de 7,8 ± 3,6 ans. Le type histologique le plus fréquent du syndrome néphrotique était la néphropathie à lésions minimales (NLM), obser vée chez 35 (74,5 %) enfants, suivie de la glomérulonéphrite membranoproliférative (GMPN) chez 5 (10,6 %) et du sclérose segmentaire et focale (SSF) chez 2 (4,3 %). Parmi les 35 patients atteints de NLM, 31 (88,6 %) étaient cortico-sensibles et 4 (11,4 %) cortico-résistants. CONCLUSION: La principale caractéristique histopathologique du syndrome néphrotique de l'enfant était la néphropathie à lésions minimales, qui était principalement cortico-sensible. MOTS-CLÉS: Syndrome néphrotique, Enfant, Histopathologie, Nigeria.
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Nefrosis Lipoidea , Síndrome Nefrótico , Humanos , Masculino , Niño , Femenino , Nigeria/epidemiología , Adolescente , Preescolar , Síndrome Nefrótico/patología , Síndrome Nefrótico/epidemiología , Estudios Prospectivos , Nefrosis Lipoidea/patología , Nefrosis Lipoidea/epidemiología , Biopsia/métodos , Glomeruloesclerosis Focal y Segmentaria/patología , Glomeruloesclerosis Focal y Segmentaria/epidemiología , Centros de Atención Terciaria , Glomerulonefritis Membranoproliferativa/patología , Glomerulonefritis Membranoproliferativa/epidemiología , Riñón/patologíaRESUMEN
BACKGROUND: Minimal Change Disease (MCD) and Focal Segmental Glomerulosclerosis (FSGS) are a spectrum of disease causing the nephrotic syndrome (NS), characterised by proteinuria with debilitating oedema, as well as a high risk of venous thromboembolic disease and infection. Untreated, 50-60% patients with FSGS progress to end stage kidney disease after 5 years. These diseases respond to immunosuppression with high dose glucocorticoids, but 75% will relapse as the glucocorticoids are withdrawn, leading to significant morbidity associated with prolonged use. In children, the B cell depleting monoclonal antibody rituximab reduces relapse risk, but this drug has not been tested in randomised controlled trial in adults. METHODS: 130-150 adults with new or relapsing MCD/FSGS, from UK Renal Units, are being randomised to receive either rituximab (two 1 g infusions two weeks apart) or placebo. Partipicipants are recruited when they present with nephrosis, and all are treated with glucocorticoids as per KDIGO guidelines. Once in remission, prednisolone is withdrawn according to a pre-specified regimen. If in remission at 6 months, participants receive a further dose of trial drug. If they relapse, they are unblinded, and if they have received placebo, they are offered open label rituximab with protocolised prednisolone as in the main phase of the trial. The primary end point is time from remission to relapse. A number of secondary endpoints will be assessed including the effect of rituximab on: (1) NHS and societal resource use and hence cost: (2) safety: (3) other measures of efficacy, such as achievement of partial and complete remission of NS and the preservation of renal function: (4) health status of participant. TRIAL REGISTRATION: TURING received ethical approval on 14 Jun 2019 - REC reference: 19/LO/0738. It is registered on EudraCT, with ID number: 2018-004611-50, with a start date of 2019-06-14.
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Análisis Costo-Beneficio , Glomeruloesclerosis Focal y Segmentaria , Nefrosis Lipoidea , Síndrome Nefrótico , Rituximab , Humanos , Rituximab/uso terapéutico , Método Doble Ciego , Nefrosis Lipoidea/tratamiento farmacológico , Glomeruloesclerosis Focal y Segmentaria/tratamiento farmacológico , Síndrome Nefrótico/tratamiento farmacológico , Recurrencia , Factores Inmunológicos/uso terapéutico , Factores Inmunológicos/economía , Resultado del Tratamiento , Adulto , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Patients with nephrotic syndrome (NS) present with edema, proteinuria, hypoalbuminemia, and hyperlipidemia. In children, the most common causes are idiopathic minimal change disease and focal segmental glomerulosclerosis (FSGS). In adults, FSGS and membranous nephropathy (MN) are the most common primary causes. There are numerous secondary causes, including diabetes, amyloidosis, systemic lupus erythematosus, hematologic malignancies, and infections. In addition to confirming the diagnosis of NS by measuring proteinuria and serum albumin and lipid levels, evaluation should assess for secondary causes. In children, most cases are due to minimal change disease, which is responsive to steroid treatment. A glucocorticoid should be prescribed for children younger than 12 years. If the patient improves with steroid treatment, no biopsy is needed. If the patient does not improve, genetic testing and kidney biopsy are warranted to determine the diagnosis. In adults, biopsy typically is indicated for diagnosis, except in patients with positive test results for serum anti-phospholipase A2 receptor antibodies. This is diagnostic of MN. For patients with NS, management of initial and infrequent recurrences involves reduction of proteinuria with glucocorticoids. Frequent recurrences and/or the inability to discontinue glucocorticoids requires alternative therapies. Steroid-resistant NS also requires use of alternative therapies. Long-term NS management includes dietary sodium restriction, edema management, and blood pressure control. Thromboembolism prophylaxis should be considered for patients with NS and high risk of thromboembolism, particularly those with MN.
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Síndrome Nefrótico , Humanos , Síndrome Nefrótico/diagnóstico , Síndrome Nefrótico/etiología , Síndrome Nefrótico/terapia , Glomeruloesclerosis Focal y Segmentaria/diagnóstico , Glomeruloesclerosis Focal y Segmentaria/terapia , Glomerulonefritis Membranosa/diagnóstico , Glomerulonefritis Membranosa/terapia , Glucocorticoides/uso terapéutico , Adulto , Niño , Nefrosis Lipoidea/diagnóstico , Nefrosis Lipoidea/terapia , Proteinuria/diagnóstico , Proteinuria/etiologíaRESUMEN
Background: Minimal change disease (MCD) is a common cause of adult nephrotic syndrome. Most adults with MCD achieve complete remission (CR) after initial steroid therapy. However, approximately 30% of adults who respond to steroids experience frequent relapses, becoming steroid-dependent and potentially developing refractory MCD. Treating refractory MCD in adults poses a significant challenge. Main body: A 37-year-old woman presented to the nephrology department with a 6-year history of MCD. The diagnosis of MCD was confirmed via renal biopsy. She initially achieved CR with steroid treatment but experienced relapse during steroid tapering. Subsequent CR was achieved with a regimen of steroids and tacrolimus although multiple relapses occurred. Rituximab led to another CR, but its maintenance lasted only 6 months. The response to subsequent rituximab treatments was unsatisfactory. Ultimately, obinutuzumab was selected, resulting in the induction and maintenance of CR for 12 months. Conclusions: This case demonstrates the successful treatment of frequently relapsed, steroid-dependent, and rituximab-resistant MCD with obinutuzumab. Obinutuzumab is a promising therapeutic option for rituximab-resistant MCD.
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Anticuerpos Monoclonales Humanizados , Nefrosis Lipoidea , Rituximab , Humanos , Adulto , Femenino , Nefrosis Lipoidea/tratamiento farmacológico , Rituximab/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Resistencia a Medicamentos , Resultado del Tratamiento , Inducción de Remisión , RecurrenciaAsunto(s)
Resistencia a Medicamentos , Fiebre Mediterránea Familiar , Nefrosis Lipoidea , Humanos , Fiebre Mediterránea Familiar/complicaciones , Fiebre Mediterránea Familiar/tratamiento farmacológico , Nefrosis Lipoidea/tratamiento farmacológico , Nefrosis Lipoidea/complicaciones , Masculino , FemeninoRESUMEN
BACKGROUND: There have been some shifts in the frequency and distribution of biopsy-proven renal diseases in China over recent years. The aim of the study was to investigate the changing spectrum of renal diseases from the view of kidney biopsy data in a single center of China. METHODS AND RESULTS: A total of 10,996 cases of native renal biopsies from patients aged ≥15 years old in Huashan Hospital, Fudan University, between 2008 and 2018 were analyzed retrospectively. The results showed that primary glomerular nephropathy (PGN) remained the most common biopsy-proven renal disease (69.42% of total), with IgA nephropathy (IgAN) accounting for 44.40% of PGN, membranous nephropathy (MN) for 28.55%, minimal change disease (MCD) for 13.26% and focal segmental glomerulosclerosis (FSGS) for 8.00%. During the study period, the proportion of MN in PGN appeared an increasing tendency, while that of IgAN and MCD remained stable and that of FSGS showed a decline. Secondary glomerular nephropathy (SGN) constituted 21.54% of total cases, among which the leading two diseases were lupus nephritis (LN) and Henoch-Schonlein purpura nephritis (HSN) which accounted for 41.08% and 19.11% respectively. CONCLUSIONS: The 11-year retrospective study revealed that PGN was the predominant histologic diagnosis among patients undergoing renal biopsy and the most frequent type of PGN remained to be IgAN, followed by MN which increased dramatically.
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Glomerulonefritis por IGA , Glomerulonefritis Membranosa , Glomeruloesclerosis Focal y Segmentaria , Riñón , Nefrosis Lipoidea , Humanos , China/epidemiología , Masculino , Estudios Retrospectivos , Adulto , Femenino , Persona de Mediana Edad , Biopsia/estadística & datos numéricos , Glomerulonefritis Membranosa/patología , Glomerulonefritis Membranosa/epidemiología , Glomerulonefritis por IGA/patología , Glomerulonefritis por IGA/epidemiología , Glomeruloesclerosis Focal y Segmentaria/patología , Glomeruloesclerosis Focal y Segmentaria/epidemiología , Adulto Joven , Nefrosis Lipoidea/patología , Nefrosis Lipoidea/epidemiología , Riñón/patología , Adolescente , Nefritis Lúpica/patología , Nefritis Lúpica/epidemiología , Anciano , Vasculitis por IgA/patología , Vasculitis por IgA/epidemiología , Vasculitis por IgA/diagnóstico , Glomerulonefritis/patología , Glomerulonefritis/epidemiología , Enfermedades Renales/patología , Enfermedades Renales/epidemiología , Enfermedades Renales/diagnósticoRESUMEN
Minimal change disease represents a common cause of nephrotic syndrome in both pediatric and adult patients. Although much remains to be discovered, there have been significant recent advancements in our understanding of the pathophysiology of minimal change disease, including the discovery of antinephrin antibodies as a marker for diagnosis of disease. Here we will review what is known about the pathophysiology, treatment, and prognosis of minimal change disease and the differences between pediatric and adult patients. Recent advances in our understanding of the mechanisms of disease will be noted. We will discuss how this may change the treatment of minimal change disease going forward and what remains to be studied.
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Nefrosis Lipoidea , Humanos , Nefrosis Lipoidea/diagnóstico , Nefrosis Lipoidea/fisiopatología , Nefrosis Lipoidea/inmunología , Niño , Adulto , PronósticoRESUMEN
Primary glomerulonephritis comprises several renal-limited diseases that can cause haematoproteinuria, chronic kidney disease, nephrosis and end stage kidney disease. The most common of these are IgA nephropathy (IgAN), primary membranous nephropathy (PMN), Focal Segmental Glomerulosclerosis (FSGS) and Minimal Change Disease (MCD). Although rare, these diseases cause a significant burden to health care systems, given the high cost of treating End Stage Kidney Disease (ESKD) with dialysis or transplantation. Until recently, the pathogenesis of primary gloerulonephritis has remained obscure. However, recent advances in understanding of how these diseases evolve has led to the introduction of novel therapeutic agents. Trials are underway or have recently completed that have huge implications for the standard of care for the primary glomerulonephritidies, and should dramatically reduce the number of patients who progress onto end stage kidney disease. This article reviews the international Kidney Disease Improving Global Outcomes (KDIGO) guidelines for the treatment of IgAN, PMN, FSGS and MCD, as well as recent research on pathogenesis and treatment.
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Glomerulonefritis por IGA , Glomerulonefritis , Glomeruloesclerosis Focal y Segmentaria , Humanos , Glomerulonefritis/terapia , Glomerulonefritis/diagnóstico , Glomeruloesclerosis Focal y Segmentaria/terapia , Glomerulonefritis por IGA/terapia , Glomerulonefritis por IGA/diagnóstico , Glomerulonefritis Membranosa/terapia , Nefrosis Lipoidea/terapia , Nefrosis Lipoidea/diagnóstico , Inmunosupresores/uso terapéutico , Guías de Práctica Clínica como AsuntoRESUMEN
Primary glomerular disease (PGD) is an idiopathic cause of renal glomerular lesions that is characterized by proteinuria or hematuria and is the leading cause of chronic kidney disease (CKD). The identification of circulating biomarkers for the diagnosis of PGD requires a thorough understanding of the metabolic defects involved. In this study, ultra-high performance liquid chromatography-tandem mass spectrometry was performed to characterize the amino acid (AA) profiles of patients with pathologically diagnosed PGD, including minimal change disease (MCD), focal segmental glomerular sclerosis (FSGS), membranous nephropathy, and immunoglobulin A nephropathy. The plasma concentrations of asparagine and ornithine were low, and that of aspartic acid was high, in patients with all the pathologic types of PGD, compared to healthy controls. Two distinct diagnostic models were generated using the differential plasma AA profiles using logistic regression and receiver operating characteristic analyses, with areas under the curves of 1.000 and accuracies up to 100.0% in patients with MCD and FSGS. In conclusion, the progression of PGD is associated with alterations in AA profiles, The present findings provide a theoretical basis for the use of AAs as a non-invasive, real-time, rapid, and simple biomarker for the diagnosis of various pathologic types of PGD.
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Aminoácidos , Biomarcadores , Metabolómica , Humanos , Femenino , Masculino , Aminoácidos/sangre , Adulto , Metabolómica/métodos , Persona de Mediana Edad , Biomarcadores/sangre , Glomeruloesclerosis Focal y Segmentaria/sangre , Glomeruloesclerosis Focal y Segmentaria/diagnóstico , Nefrosis Lipoidea/sangre , Nefrosis Lipoidea/diagnóstico , Glomerulonefritis Membranosa/sangre , Glomerulonefritis Membranosa/diagnóstico , Espectrometría de Masas en Tándem , Cromatografía Líquida de Alta Presión , Glomerulonefritis por IGA/sangre , Glomerulonefritis por IGA/diagnóstico , Glomérulos Renales/metabolismo , Glomérulos Renales/patologíaRESUMEN
The COVID-19 era has been a reminder to clinicians around the world of the important role that viral infections play in promoting glomerular disease. Several viral infections including human immunodeficiency virus (HIV), severe acute respiratory syndrome coronavirus 2, Epstein-Barr virus, cytomegalovirus, and parvovirus B19 can cause podocyte injury and present with a collapsing glomerulopathy (CG) variant of focal segmental glomerulosclerosis or minimal change disease. CG associated with COVID-19 has been termed COVID-19-associated nephropathy due to its striking resemblance to HIV-associated nephropathy. Host susceptibility is a major determinant of viral infection-associated CG, and the presence of two APOL1 risk variants explains most of the racial predilection to viral-associated CG observed in individuals of African ancestry. Interactions between APOL1 risk variants, viral genes, and the systemic inflammatory response to viral infection all contribute to kidney injury. This review will summarize our current knowledge of viral infection-associated CG, focusing primarily on the clinical presentation, histological features, mechanisms, and disease course of HIV-associated nephropathy and COVID-19-associated nephropathy.
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COVID-19 , Glomeruloesclerosis Focal y Segmentaria , SARS-CoV-2 , Humanos , COVID-19/patología , COVID-19/complicaciones , COVID-19/virología , Glomeruloesclerosis Focal y Segmentaria/patología , Glomeruloesclerosis Focal y Segmentaria/virología , Glomeruloesclerosis Focal y Segmentaria/etiología , SARS-CoV-2/patogenicidad , Infecciones por VIH/complicaciones , Infecciones por VIH/patología , Apolipoproteína L1/genética , Virosis/complicaciones , Virosis/patología , Virosis/virología , Nefrosis Lipoidea/patología , Nefrosis Lipoidea/virología , Nefropatía Asociada a SIDA/patología , Nefropatía Asociada a SIDA/virología , Nefropatía Asociada a SIDA/genética , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/virologíaRESUMEN
The mechanism underlying podocyte dysfunction in minimal change disease (MCD) remains unknown. This study aimed to shed light on the potential pathophysiology of MCD using glomerular proteomic analysis. Shotgun proteomics using label-free quantitative mass spectrometry was performed on formalin-fixed, paraffin-embedded (FFPE) renal biopsies from two groups of samples: control (CTR) and MCD. Glomeruli were excised from FFPE renal biopsies using laser capture microdissection (LCM), and a single-pot solid-phase-enhanced sample preparation (SP3) digestion method was used to improve yield and protein identifications. Principal component analysis (PCA) revealed a distinct separation between the CTR and MCD groups. Forty-eight proteins with different abundance between the two groups (p-value ≤ 0.05 and |FC| ≥ 1.5) were identified. These may represent differences in podocyte structure, as well as changes in endothelial or mesangial cells and extracellular matrix, and some were indeed found in several of these structures. However, most differentially expressed proteins were linked to the podocyte cytoskeleton and its dynamics. Some of these proteins are known to be involved in focal adhesion (NID1 and ITGA3) or slit diaphragm signaling (ANXA2, TJP1 and MYO1C), while others are structural components of the actin and microtubule cytoskeleton of podocytes (ACTR3 and NES). This study suggests the potential of mass spectrometry-based shotgun proteomic analysis with LCM glomeruli to yield valuable insights into the pathogenesis of podocytopathies like MCD. The most significantly dysregulated proteins in MCD could be attributable to cytoskeleton dysfunction or may be a compensatory response to cytoskeleton malfunction caused by various triggers.
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Glomérulos Renales , Nefrosis Lipoidea , Podocitos , Proteómica , Humanos , Nefrosis Lipoidea/metabolismo , Nefrosis Lipoidea/patología , Proteómica/métodos , Podocitos/metabolismo , Podocitos/patología , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Masculino , Femenino , Adulto , Proteoma/metabolismo , Proteoma/análisis , Captura por Microdisección con Láser , Persona de Mediana EdadRESUMEN
INTRODUCTION: Membranous nephropathy (MN) is the most common cause of primary nephrotic syndrome in adults (20-30%). Light microscopy shows thickening of glomerular basement membrane with appearance of spikes. These histological findings are not evident in early forms, in which case the granular deposition pattern of IgG and/or C3 in the basement membrane by immunofluorescence (IF) constitutes the diagnostic tool that allows to differentiate it from minimal change disease (MCD). Complement system plays a key role in the pathophysiology of MN. C4d is a degradation product and a marker of the complement system activation. C4d labelling by immunohistochemical (HI) technique can help in the differential diagnosis between both glomerulopathies NM and MCD when the material for IF is insufficient and light microscopy is normal. Our objective was to explore the discrimination power of C4d to differentiate between MN and MCD in renal biopsy material. METHODS: Paraffin-embedded samples were recovered from renal biopsies with a diagnosis of MN and MCD performed between 1/1/2008 and 4/1/2019. IH staining was performed by immunoperoxidase technique using a rabbit anti-human C4d polyclonal antibody. RESULTS: In all cases with MN (n = 27, 15 males) with a median age of 63 (range: 18-87) years, C4d deposits were detected. In 21 cases with MCD (12 males) with a median age of 51 (range: 18-87) years, the C4d marking was negative in every samples. CONCLUSION: The results indicate that the marking of the renal biopsy with C4d is a useful tool for the differential diagnosis between NM and MCD.
Introducción: La nefropatía membranosa (NM) es la causa más frecuente de síndrome nefrótico primario en adultos (20-30%). En la microscopia óptica se observa engrosamiento de membrana basal glomerular con aparición de espigas. Estos hallazgos histológicos no son evidentes en formas tempranas, en cuyo caso el patrón de depósito granular de IgG y/o C3 en la membrana basal por inmunofluorescencia (IF) permite diferenciarla de enfermedad por cambios mínimos (ECM). El sistema del complemento juega un papel central en la fisiopatología de la NM. C4d es producto de degradación y un marcador de la activación del complemento. La marcación con C4d en muestras de biopsias renales, por técnica de inmunohistoquímica (IH) puede colaborar en el diagnóstico diferencial entre ambas glomerulopatías. Nuestro objetivo fue explorar el poder de discriminación del C4d para diferenciar NM de ECM en material de biopsias renales. Métodos: Se recuperaron muestras en parafina de biopsias renales con diagnóstico de NM y ECM realizados entre 1/1/2008 y 1/4/2019. Se realizaron tinciones de IH por técnica de inmunoperoxidasa con C4d usando un anticuerpo policlonal antihumano de conejo. Resultados: En todos los casos con NM (n = 27, 15 hombres) con mediana de edad de 63 (rango: 18-86) años se detectaron depósitos de C4d. En los 21 casos con ECM (12 hombres) con mediana de edad de 51 (rango: 18-87) años la marcación de C4d fue negativa. Conclusión: Los resultados indican que la marcación de la biopsia renal con C4d es una herramienta útil para el diagnóstico diferencial entre NM y ECM.
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Complemento C4b , Glomerulonefritis Membranosa , Glomerulonefritis Membranosa/diagnóstico , Glomerulonefritis Membranosa/patología , Glomerulonefritis Membranosa/inmunología , Humanos , Masculino , Adulto , Persona de Mediana Edad , Femenino , Anciano , Complemento C4b/análisis , Adulto Joven , Diagnóstico Diferencial , Anciano de 80 o más Años , Adolescente , Biopsia , Biomarcadores/análisis , Nefrosis Lipoidea/patología , Nefrosis Lipoidea/diagnóstico , Fragmentos de Péptidos/análisis , Estudios RetrospectivosRESUMEN
Glomerulonephritis (GN) is characterized by podocyte injury or glomerular filtration dysfunction, which results in proteinuria and eventual loss of kidney function. Progress in studying the mechanism of GN, and developing an effective therapy, has been limited by the absence of suitable in vitro models that can closely recapitulate human physiological responses. We developed a microfluidic glomerulus-on-a-chip device that can recapitulate the physiological environment to construct a functional filtration barrier, with which we investigated biological changes in podocytes and dynamic alterations in the permeability of the glomerular filtration barrier (GFB) on a chip. We also evaluated the potential of GN-mimicking devices as a model for predicting responses to human GN. Glomerular endothelial cells and podocytes successfully formed intact monolayers on opposite sides of the membrane in our chip device. Permselectivity analysis confirmed that the chip was constituted by a functional GFB that could accurately perform differential clearance of albumin and dextran. Reduction in cell viability resulting from damage was observed in all serum-induced GN models. The expression of podocyte-specific marker WT1 was also decreased. Albumin permeability was increased in most models of serum-induced IgA nephropathy (IgAN) and membranous nephropathy (MN). However, sera from patients with minimal change disease (MCD) or lupus nephritis (LN) did not induce a loss of permeability. This glomerulus-on-a-chip system may provide a platform of glomerular cell culture for in vitro GFB in formation of a functional three-dimensional glomerular structure. Establishing a disease model of GN on a chip could accelerate our understanding of pathophysiological mechanisms of glomerulopathy.
Asunto(s)
Glomerulonefritis , Glomérulos Renales , Dispositivos Laboratorio en un Chip , Podocitos , Humanos , Podocitos/metabolismo , Podocitos/patología , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Glomerulonefritis/metabolismo , Glomerulonefritis/fisiopatología , Glomerulonefritis/patología , Barrera de Filtración Glomerular/metabolismo , Glomerulonefritis Membranosa/metabolismo , Glomerulonefritis Membranosa/patología , Glomerulonefritis Membranosa/fisiopatología , Glomerulonefritis por IGA/metabolismo , Glomerulonefritis por IGA/patología , Glomerulonefritis por IGA/fisiopatología , Permeabilidad , Células Endoteliales/metabolismo , Células Endoteliales/patología , Nefritis Lúpica/metabolismo , Nefritis Lúpica/patología , Nefritis Lúpica/fisiopatología , Supervivencia Celular , Nefrosis Lipoidea/metabolismo , Nefrosis Lipoidea/patología , Nefrosis Lipoidea/fisiopatologíaAsunto(s)
Eosinofilia , Arteritis de Células Gigantes , Nefrosis Lipoidea , Humanos , Eosinofilia/diagnóstico , Eosinofilia/tratamiento farmacológico , Arteritis de Células Gigantes/complicaciones , Arteritis de Células Gigantes/diagnóstico , Arteritis de Células Gigantes/tratamiento farmacológico , Glucocorticoides/uso terapéutico , Inmunosupresores/uso terapéutico , Nefrosis Lipoidea/diagnóstico , Nefrosis Lipoidea/tratamiento farmacológico , Nefrosis Lipoidea/complicaciones , Resultado del TratamientoRESUMEN
Idiopathic nephrotic syndrome (NS) is a heterogeneous group of glomerular disorders which includes two major phenotypes: minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). MCD and FSGS are classic types of primary podocytopathies. We aimed to explore the molecular mechanisms in NS triggered by primary podocytopathies and evaluate diagnostic value of the selected proteomic signatures by analyzing blood proteome profiling. Totally, we recruited 90 participants in two cohorts. The first cohort was analyzed using label-free quantitative (LFQ) proteomics to discover differential expressed proteins and identify enriched biological process in NS which were further studied in relation to clinical markers of kidney injury. The second cohort was analyzed using parallel reaction monitoring-based quantitative proteomics to verify the data of LFQ proteomics and assess the diagnostic performance of the selected proteins using receiver-operating characteristic curve analysis. Several biological processes (such as immune response, cell adhesion, and response to hypoxia) were found to be associated with kidney injury during MCD and FSGS. Moreover, three proteins (CSF1, APOC3, and LDLR) had over 90% sensitivity and specificity in detecting adult NS triggered by primary podocytopathies. The identified biological processes may play a crucial role in MCD and FSGS pathogenesis. The three blood protein markers are promising for diagnosing adult NS triggered by primary podocytopathies.
Asunto(s)
Biomarcadores , Glomeruloesclerosis Focal y Segmentaria , Nefrosis Lipoidea , Síndrome Nefrótico , Podocitos , Proteómica , Humanos , Síndrome Nefrótico/sangre , Síndrome Nefrótico/diagnóstico , Síndrome Nefrótico/metabolismo , Proteómica/métodos , Adulto , Glomeruloesclerosis Focal y Segmentaria/diagnóstico , Glomeruloesclerosis Focal y Segmentaria/metabolismo , Glomeruloesclerosis Focal y Segmentaria/sangre , Glomeruloesclerosis Focal y Segmentaria/patología , Femenino , Nefrosis Lipoidea/diagnóstico , Nefrosis Lipoidea/metabolismo , Masculino , Podocitos/metabolismo , Podocitos/patología , Biomarcadores/sangre , Proteoma/análisis , Persona de Mediana Edad , Estudios de Cohortes , Curva ROCRESUMEN
BACKGROUND: Minimal change disease and primary focal segmental glomerulosclerosis in adults, along with idiopathic nephrotic syndrome in children, are immune-mediated podocytopathies that lead to nephrotic syndrome. Autoantibodies targeting nephrin have been found in patients with minimal change disease, but their clinical and pathophysiological roles are unclear. METHODS: We conducted a multicenter study to analyze antinephrin autoantibodies in adults with glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, IgA nephropathy, antineutrophil cytoplasmic antibody-associated glomerulonephritis, and lupus nephritis, as well as in children with idiopathic nephrotic syndrome and in controls. We also created an experimental mouse model through active immunization with recombinant murine nephrin. RESULTS: The study included 539 patients (357 adults and 182 children) and 117 controls. Among the adults, antinephrin autoantibodies were found in 46 of the 105 patients (44%) with minimal change disease, 7 of 74 (9%) with primary focal segmental glomerulosclerosis, and only in rare cases among the patients with other conditions. Of the 182 children with idiopathic nephrotic syndrome, 94 (52%) had detectable antinephrin autoantibodies. In the subgroup of patients with active minimal change disease or idiopathic nephrotic syndrome who were not receiving immunosuppressive treatment, the prevalence of antinephrin autoantibodies was as high as 69% and 90%, respectively. At study inclusion and during follow-up, antinephrin autoantibody levels were correlated with disease activity. Experimental immunization induced a nephrotic syndrome, a minimal change disease-like phenotype, IgG localization to the podocyte slit diaphragm, nephrin phosphorylation, and severe cytoskeletal changes in mice. CONCLUSIONS: In this study, circulating antinephrin autoantibodies were common in patients with minimal change disease or idiopathic nephrotic syndrome and appeared to be markers of disease activity. Their binding at the slit diaphragm induced podocyte dysfunction and nephrotic syndrome, which highlights their pathophysiological significance. (Funded by Deutsche Forschungsgemeinschaft and others.).
Asunto(s)
Autoanticuerpos , Proteínas de la Membrana , Síndrome Nefrótico , Podocitos , Proteínas de la Membrana/inmunología , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Humanos , Animales , Ratones , Niño , Podocitos/inmunología , Adulto , Síndrome Nefrótico/inmunología , Masculino , Femenino , Persona de Mediana Edad , Modelos Animales de Enfermedad , Adolescente , Nefrosis Lipoidea/inmunología , Preescolar , Glomeruloesclerosis Focal y Segmentaria/inmunología , Adulto Joven , AncianoRESUMEN
PURPOSE: To evaluate the differences in clinicopathological features and outcomes of IgA nephropathy (IgAN) patients with and without nephrotic syndrome. METHODS: In this retrospective cohort study, IgAN patients from January 2006 to December 2011 in the First Affiliated Hospital of Sun Yat-sen University were enrolled and followed up to Dec 31, 2013. Logistic and Cox regression were conducted to evaluate the associated factors of nephrotic syndrome (NS) and its relation with outcomes of creatinine doubling and progression to end-stage kidney disease (ESKD). RESULTS: A total of 1413 patients with IgAN were enrolled in this study, 57 (4.0%) of whom exhibited NS. Meanwhile, 13 (22.8%) of NS IgAN patients had minimal change disease (MCD). Logistic regression showed that more presence of hypertension, less glomerular sclerosis, less tubular atrophy/interstitial fibrosis, and lower density of IgA deposition in mesangial region were significantly associated with NS IgAN that were independent of age and gender. In addition, a total of 921 patients (890 with non-NS IgAN and 31 with NS IgAN) were followed up to Dec 31, 2013. After adjusting for age, sex, baseline estimated glomerular rate, hypertension and hemoglobin, no significant difference was observed in outcomes of serum creatinine doubling and ESKD between patients with or without NS IgAN. CONCLUSIONS: Prevalence of NS IgAN patients was 4.0%, and 22.8% of them had MCD. Patients with NS IgAN had more severe clinical but less severe pathological features. However, outcomes of serum creatinine doubling and ESKD were not significantly different between patients with or without NS IgAN.
Asunto(s)
Glomerulonefritis por IGA , Fallo Renal Crónico , Síndrome Nefrótico , Humanos , Glomerulonefritis por IGA/patología , Glomerulonefritis por IGA/complicaciones , Glomerulonefritis por IGA/sangre , Masculino , Femenino , Estudios Retrospectivos , Adulto , Síndrome Nefrótico/complicaciones , Síndrome Nefrótico/patología , Síndrome Nefrótico/sangre , Fallo Renal Crónico/complicaciones , Persona de Mediana Edad , Progresión de la Enfermedad , Creatinina/sangre , Hipertensión/complicaciones , Nefrosis Lipoidea/patología , Nefrosis Lipoidea/complicaciones , Adulto JovenRESUMEN
BACKGROUND: Idiopathic nephrotic syndrome (INS) is the most common glomerular disease in children. We performed this study to report histopathological findings, the correlation between clinical and histopathological features, and the response to steroids and other immunosuppressive drugs and outcomes in Syrian children with INS. METHODS: A single-center retrospective observational cohort study was conducted at Children's University Hospital in Damascus, and included all patients aged 1-14 years, admitted from January 2013 to December 2022, with INS and who underwent kidney biopsy. RESULTS: The study included 109 patients, with a male/female ratio of 1.13:1, and a median age of 5 years with interquartile range (2.8-10). The main indication of kidney biopsy was steroid-resistant nephrotic syndrome (SRNS) (57.8%). The main histopathological patterns were minimal change disease (MCD) (45%) and focal segmental glomerulosclerosis (FSGS) (37.6%). FSGS was the most common histopathological pattern in SRNS (44.3%). In SRNS, we used calcineurin inhibitors to induce remission. Tacrolimus was used in 49 patients with response rate (complete remission of proteinuria) of 69.4% and cyclosporine in 20 patients with response rate of 50%. In steroid-dependent nephrotic syndrome (SDNS), we used mycophenolate mofetil (MMF) and cyclophosphamide to prevent relapses; MMF was used in 9 patients with response rate (maintaining sustained remission) of 89% and cyclophosphamide in 3 patients with response rate of 66.7%. Rituximab was used in four patients with FSGS, two SRNS patients and two SDNS patients, with sustained remission rate of 100%. Fifteen patients (13.7%) progressed to chronic kidney disease stage 5. Of them, 7 patients had FSGS and 8 patients had focal and global glomerulosclerosis;14 of them were steroid-resistant and one patient was steroid-dependent with persistent relapses. The most common outcome was sustained remission (47%) in MCD and frequent relapses (31.7%) in FSGS. CONCLUSIONS: FSGS was the most common histopathological pattern in idiopathic SRNS and had the worst prognosis. Calcineurin inhibitors could be an effective therapy to induce complete remission in SRNS. Rituximab may be an effective treatment to achieve sustained remission in SDNS and frequently relapsing NS and may have a potential role in SRNS with further studies required.