Hallazgos ultraestructurales renales de pacientes con nefritis intersticial crónica de las comunidades agrícolas en El Salvador / Renal ultrastructural findings of patients with chronic interstitial nephritis from farming communities in El Salvador

Introducción: Desde hace 20 años se presenta en Centroamérica una enfermedad renal crónica que fundamentalmente afecta a hombres agricultores y no asociada a las causas tradicionales. Se caracteriza por presentar una nefritis intersticial crónica, en tanto las características ultraestructurales no se conocen con exactitud. En su origen se invoca el uso de agroquímicos y otros agentes nefrotóxicos, la deshidratación crónica, el consumo de medicamentos, entre otros factores. Objetivo: Describir las características ultraestructurales de la nefritis intersticial crónica en comunidades agrícolas. Método: Se realizó un estudio descriptivo de corte transversal. Se estudiaron muestras de biopsias renales de ocho pacientes con diagnóstico de nefritis intersticial crónica de las comunidades agrícolas. Resultados: De los ocho pacientes estudiados, dos (25 por ciento) trabajaban en labores agrícolas y cinco eran del sexo femenino (62,5 por ciento). Dos de los pacientes (25 por ciento) presentaban una enfermedad renal crónica estadio 2, y seis (75 por ciento) estadio 3. En cinco pacientes se hallaron fagolisosomas con presencia de componente lipídico entremezclado con material electrodenso en células del túbulo distal. En igual cantidad de pacientes se observaron cuerpos mieloides con zonas laminadas y núcleo central en células de túbulo proximal y de los vasos sanguíneos. Conclusiones: En pacientes de comunidades agrícolas que padecen nefritis intersticial crónica se evidencian fagolisosomas y estructuras mieloides en túbulos y vasos renales, cuyo contenido y origen se desconocen(AU)

Introduction: Chronic kidney disease mainly affecting male farmers and not associated to traditional causes has been present in Central America for twenty years. The condition is characterized by the presence of chronic interstitial nephritis, but its ultrastructural features are not fully known. Factors suggested as responsible for its occurrence include the use of agrochemicals and other nephrotoxic agents, chronic dehydration and medicine consumption. Objective: Describe the ultrastructural characteristics of chronic interstitial nephritis in farming communities. Method: A cross-sectional descriptive study was conducted of renal biopsy samples from eight patients diagnosed with chronic interstitial nephritis in farming communities. Results: Of the eight patients studied, two (25 percent) were farm workers and five (62.5percent) were female. Two of the patients (25 percent) had stage 2 and six (75 percent) stage 3 chronic kidney disease. In five patients evidence was found of phagolysosomes with lipid component mixed with electrodense material in distal tubule cells. An equal number of patients had myeloid bodies with laminated areas and central nucleus in proximal tubule and blood vessel cells. Conclusions: Evidence of phagolysosomes and myeloid structures of unknown content and origin was found in renal tubules and vessels of patients from farming communities diagnosed with chronic interstitial nephritis(AU)

Microangiopatía trombótica/síndrome hemolítico urémico. Actualización de sus características histopatológicas / Thrombotic microangiopathy/haemolytic uraemic syndrome. Histopathology update

La microangiopatía trombótica (MAT) comprende y engloba diferentes entidades conocidas como síndrome hemolítico urémico (SHU) y púrpura trombótica trombocitopénica (PTT). Las características histopatológicas han permanecido constantes a lo largo de la historia y consisten en la afectación típica glomerular con presencia de dobles contornos, mesangiólisis y microtrombos. Hay una aceptación general de que el daño vascular tiene relación con el pronóstico. La ultraestructura, junto con la histología convencional, demuestra la importante patología del capilar y de la célula endotelial. Un estudio completo histopatológico de la biopsia renal con utilización del microscopio electrónico es útil para confirmar la sospecha clínica y manifiesta los mecanismos patogénicos del daño de la microcirculación. Es precisamente la estrecha similitud ultraestructural y con microscopio óptico entre MAT y glomerulopatía del trasplante (GPTR) lo que permite defender que ambas entidades participan del mismo mecanismo etiopatogénico en donde la célula endotelial es el elemento diana. Los recientes avances en la patogenia del SHU atípico, su relación con el sistema del complemento y el descubrimiento de dianas terapéuticas específicas han impulsado el interés por el estudio de la MAT y la importancia de la biopsia renal

Thrombotic microangiopathy (TMA) encompasses different entities known as haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). The histopathological characteristics have remained constant since the initial description and consist in glomerular-type affectation with the presence of double contours, mesangiolysis and microthrombi. It is generally accepted that the vascular damage is related to the prognosis. Ultrastructure, together with conventional histology, shows notable changes in both capillaries and endothelial cells. A comprehensive histopathological study of the renal biopsy, using electronmicroscopy, is useful in the confirmation of a clinical suspicion and demonstrates the pathogenetic mechanisms in the microcirculatory damage. The close resemblance between the ultrastructural appearance and that seen with the light microscope of TMA and transplant glomerulopathy (TG) is precisely what suggests that both entities are subject to the same etiopathogenetic mechanism in which the endothelial cell is targeted. Recent advances in the pathology of atypical HUS, its relation with complement system and the discovery of specific therapeutic targets, has rekindled an interest in the study of TMA and the importance of renal biopsy

[Thrombotic microangiopathy/haemolytic uraemic syndrome. Histopathology update]. / Microangiopatía trombótica/síndrome hemolítico urémico. Actualización de sus características histopatológicas.

Thrombotic microangiopathy (TMA) encompasses different entities known as haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). The histopathological characteristics have remained constant since the initial description and consist in glomerular-type affectation with the presence of double contours, mesangiolysis and microthrombi. It is generally accepted that the vascular damage is related to the prognosis. Ultrastructure, together with conventional histology, shows notable changes in both capillaries and endothelial cells. A comprehensive histopathological study of the renal biopsy, using electronmicroscopy, is useful in the confirmation of a clinical suspicion and demonstrates the pathogenetic mechanisms in the microcirculatory damage. The close resemblance between the ultrastructural appearance and that seen with the light microscope of TMA and transplant glomerulopathy (TG) is precisely what suggests that both entities are subject to the same etiopathogenetic mechanism in which the endothelial cell is targeted. Recent advances in the pathology of atypical HUS, its relation with complement system and the discovery of specific therapeutic targets, has rekindled an interest in the study of TMA and the importance of renal biopsy.

Anatomía patológica y nefrología. La necesidad de un cambio / Nephropathology and nephrology. The need for a change

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Anatomía patológica del trasplante renal / The pathology of renal transplants

Una valoración objetiva de la histopatología de la biopsia renal en el trasplante exige conocer todos los factores implicados. Un factor importante es tener un conocimiento de las características del órgano trasplantado sobre todo si es donante mayor de edad superior a 65años. Las características de la biopsia del donante y su afectación sobre todo vascular están relacionadas con mala función inicial del injerto. La inflamación liderada por linfocitos T es una característica de Rechazo Celular Agudo siendo importante la cuantificación del grado de tubulitis así como el área del parénquima afectada. Es importante conocer la proporción de sub-poblaciones celulares tales como células plasmáticas y macrófagos ya que pueden relacionarse con la presencia de Rechazo Humoral, mediado por anticuerpos. El estudio con inmuno-fluorescencia o inmunohistoquímica es necesario para descartar depósitos de C4d o inmunoglobulinas. La presencia de abundantes depósitos de C4d en membranas basales tubulares apoya el diagnóstico de Rechazo Humoral así como la presencia de capilaritis, glomerulitis y vasculitis son hallazgos típicos diagnósticos en casos con C4d negativo. La fibrosis intersticial, atrofia tubular y esclerosis glomerular, aunque son hallazgos inespecíficos, implican un estadío crónico. La glomerulopatía del trasplante, la multilaminación en mas de 6 capas de la membrana basal del glomérulo o del túbulo son características quasi específicas de la existencia de Rechazo Humoral crónico. La identificación de estas previas patologías así como la presencia de otras enfermedades renales glomerulares exigen el estudio con microscopio electrónico (AU)

In order to make an objective assessment of the histopathology of a renal biopsy during a kidney transplant, all the various elements involved in the process must be understood. It is important to know the characteristics of the donor organ, especially if the donor is older than 65. The histopathological features of the donor biopsy, especially its vascular status, are often related to an initial poor function of the transplanted kidney. The T lymphocyte inflammatory response is characteristic in acute cellular rejection; the degree of tubulitis, together with the amount of affected parenchyme, are important factors. The proportion of cellular sub-populations, such as plasma cells and macrophages, is also important, as they can be related to antibody-mediated humoral rejection. Immunofluorescent or immunohistochemical studies are necessary to rule out C4d deposits or immunogloblulins. The presence of abundant deposits of C4d in tubular basement membranes supports a diagnosis of humoral rejection, as does the presence of capillaritis, glomerulitis which, together with vasculitis, are typical diagnostic findings in C4d negative cases. Interstitial fibrosis, tubular atrophy and glomerular sclerosis, although non-specific, imply a chronic phase. Transplant glomerulopathy and multilamination in more than 6 layers of the tubular and glomerular basement membranes are quasi-specific characteristics of chronic humoral rejection. Electron microscopy is essential to identify of these pathologies as well as to demonstrate the presence of other glomerular renal diseases (AU)

[The pathology of renal transplants]. / Anatomía patológica del trasplante renal.

In order to make an objective assessment of the histopathology of a renal biopsy during a kidney transplant, all the various elements involved in the process must be understood. It is important to know the characteristics of the donor organ, especially if the donor is older than 65. The histopathological features of the donor biopsy, especially its vascular status, are often related to an initial poor function of the transplanted kidney. The T lymphocyte inflammatory response is characteristic in acute cellular rejection; the degree of tubulitis, together with the amount of affected parenchyme, are important factors. The proportion of cellular sub-populations, such as plasma cells and macrophages, is also important, as they can be related to antibody-mediated humoral rejection. Immunofluorescent or immunohistochemical studies are necessary to rule out C4d deposits or immunogloblulins. The presence of abundant deposits of C4d in tubular basement membranes supports a diagnosis of humoral rejection, as does the presence of capillaritis, glomerulitis which, together with vasculitis, are typical diagnostic findings in C4d negative cases. Interstitial fibrosis, tubular atrophy and glomerular sclerosis, although non-specific, imply a chronic phase. Transplant glomerulopathy and multilamination in more than 6 layers of the tubular and glomerular basement membranes are quasi-specific characteristics of chronic humoral rejection. Electron microscopy is essential to identify of these pathologies as well as to demonstrate the presence of other glomerular renal diseases.

Amiloidosis renal y tiroidea secundaria a síndrome periódico asociado a criopirinas (síndrome de Muckle-Wells) (mutación NLRP3) / Renal and thyroid amyloidosis secondary to cryopyrin associated periodic syndrome (Muckle-Wells syndrome) (NLRP3 mutation)

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Orientación diagnóstica de las enfermedades renales glomerulares / Diagnostic guidelines for glomerular disease

Un correcto abordaje en el diagnóstico de las diferentes enfermedades glomerulares exige un estudio metodológico que incluye no solo las características histopatológicas sino también conocimiento clínico. El principal objetivo de este artículo es una orientación para el diagnóstico y la clasificación de las enfermedades glomerulares atendiendo a su principal característica histopatológica, o patrón básico, y a las lesiones secundarias asociadas. Consideramos patrones básicos a: cambios mínimos, proliferación mesangial difusa, glomerulonefritis membranosa, glomerulonefritis membranoproliferativa y glomerulonefritis extracapilar. Dependiendo de la principal presentación clínica y de la inmunofluorescencia se identifican diferentes entidades nosológicas clínicas, como nefropatía IgA, nefropatía con depósitos de IgM, nefropatía por depósitos de C1q o C3 que se pueden presentar con el mismo patrón básico histológico. Igualmente, una entidad clínica como nefropatía IgA o lupus eritematoso pueden iniciarse con diferentes formas histológicas. Existen otras lesiones «cualificantes» o secundarias, generalmente segmentarias, que pueden superponerse a un determinado patrón básico. Entre estas lesiones destacamos: necrosis fibrinoide, cariorrexis, trombos capilares, presencia de leucocitos polimorfonucleares, esclerosis glomerular segmentaria o global, nódulos mesangiales y semilunas segmentarias. Estas lesiones son de gran utilidad para conocer los índices de cronicidad o de actividad en una biopsia, hecho muy importante para determinar el pronóstico y el tratamiento, independientemente del tipo básico, sobre todo en enfermedades sistémicas. El uso del microscopio electrónico es muy útil en nefropatología, pero sobre todo en las glomerulonefritis con depósitos fibrilares, microtubulares, nefritis hereditarias, formas de GMP y, más recientemente, en la glomerulopatía del trasplante(AU)

In order to reach a correct diagnosis of glomerular disease, both clinical and histopathological data need to be considered together. This article aims to provide a comprehensive guide for the diagnosis and classification of glomerular disease, outlining its main histopathological characteristics and associated secondary lesions. The main glomerular histologic pattern or main glomerular histopathologic models show minimal glomerular changes, diffuse mesangial proliferation, membranous glomerulonephritis, membranoproliferative glomerulonephritis and diffuse extracapillary glomerulonefritis. Depending on the clinical presentation and immunofluorescence, these basic histological patterns can be associated with different entities such as: IgA nephropathy, IgM, and C1q or C3 nephropathy. Other qualifying or secondary lesions, generally segmental, may also be found, which can be superimposed on a certain basic pattern. The most important of these are fibrinoid necrosis, capillary thrombi, leucocyte exudation, segmental sclerosis and segmental extracapillary proliferation. These lesions are useful in measuring the acute or chronic stage of renal disease, especially lupus nephritis and vasculitis. Transmission electron microscopy is essential in order to classify different nephropathies with fibrillary deposits and, recently, transplant-related glomerular disease(AU)

BK virus-associated urinary bladder carcinoma in transplant recipients: report of 2 cases, review of the literature, and proposed pathogenetic model.

Despite strong experimental evidence, BK polyomavirus involvement in human cancers has been controversial. We report 2 cases of kidney ± pancreas transplant recipients with evidence of BK polyomavirus reactivation, who developed aggressive urinary bladder urothelial carcinomas with adenocarcinomatous and/or micropapillary differentiation. Diffuse strong nuclear positivity for viral T antigen, p53, Ki-67, and p16 was observed in both malignancies. The BK polyomavirus role in promoting urothelial neoplasia in transplant recipients may be partly indirect, based on the demonstration by polymerase chain reaction in both tumors of BK polyomavirus with intact open reading frames and close phylogenetic clustering with known replication-competent strains, and viral capsid protein VP1 messenger RNA and intranuclear virions by electron microscopy in 1 tumor. No unique cancer-associated mutations were found, but some viral T antigen mutations were potentially associated with increased rate of viral replication and risk for "rare" carcinogenic events. The BK polyomavirus-induced profound effects on cell activation, cell cycle shift to proliferation, and apoptosis inhibition, in the context of marked immunosuppression, constitute a potentially ideal background for malignant transformation. The long time lapse between transplantation and tumor manifestation, 7 and 11 years, respectively, further supports the concept of multistep carcinogenesis cascade and long-term risk for these patients. We propose a model of changes ranging from viral reactivation to dysplasia to invasive carcinoma. Clinical vigilance is warranted for early diagnosis of BK polyomavirus-related urothelial malignancies in transplant recipients.

Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation.

Dense deposit disease (DDD) is a severe renal disease characterized by accumulation of electron-dense material in the mesangium and glomerular basement membrane. Previously, DDD has been associated with deficiency of factor H (fH), a plasma regulator of the alternative pathway (AP) of complement activation, and studies in animal models have linked pathogenesis to the massive complement factor 3 (C3) activation caused by this deficiency. Here, we identified a unique DDD pedigree that associates disease with a mutation in the C3 gene. Mutant C(3923ΔDG), which lacks 2 amino acids, could not be cleaved to C3b by the AP C3-convertase and was therefore the predominant circulating C3 protein in the patients. However, upon activation to C3b by proteases, or to C3(H2O) by spontaneous thioester hydrolysis, C(3923ΔDG) generated an active AP C3-convertase that was regulated normally by decay accelerating factor (DAF) but was resistant to decay by fH. Moreover, activated C(3b923ΔDG) and C3(H2O)(923ΔDG) were resistant to proteolysis by factor I (fI) in the presence of fH, but were efficiently inactivated in the presence of membrane cofactor protein (MCP). These characteristics cause a fluid phase-restricted AP dysregulation in the patients that continuously activated and consumed C3 produced by the normal C3 allele. These findings expose structural requirements in C3 that are critical for recognition of the substrate C3 by the AP C3-convertase and for the regulatory activities of fH, DAF, and MCP, all of which have implications for therapeutic developments.

Papel del patólogo ante los retos de la nefrología moderna. En busca de una solución / Role of the pathologist in modern nephropathology. In search of solutions

La prevalencia de las enfermedades renales que causaninsuficiencia renal crónica es una realidad preocupante, porla gran morbilidad y el elevado coste sanitario que provocan.A pesar del gran desarrollo de técnicas diagnósticas yterapéuticas que culminan con el trasplante renal, la biopsiarenal sigue siendo el mejor método diagnóstico para identificarun proceso patológico concreto. En los últimos añosesta técnica no solo es útil para el diagnóstico, sino tambiénpara establecer criterios objetivos de pronóstico y sensibilidada un determinado tratamiento, como de hecho ocurre enel trasplante. Una metodología correcta en el estudio de lapatología renal exige clásicamente una técnica depuradaque se inicia con el procesamiento tisular, continúa con elestudio de inmunofluorescencia y/o inmunohistoquímica yel análisis ultraestructural y termina con la aplicaciónpotencial de la biología molecular. Es una exigencia científicay ética para cualquier médico el rentabilizar al máximocualquier prueba diagnóstica. Pero esta metodología, que escomplicada y costosa, no será rentable si no va sumada a ladedicación y la experiencia del patólogo. El paciente, el clínicoy la misma complejidad de las enfermedades renalesexigen cada vez más a los servicios de Anatomía Patológicala subespecialización. En nuestro país, como consecuenciade nuestra planificación hospitalaria, existe una excesivadispersión de servicios y especialidades médicas queimpide en gran manera la experiencia del patólogo, sobretodo en hospitales con limitado número de biopsias. (...) (AU)

The high incidence of renal diseases leading to chronicrenal failure is a serious health problem, due to their significantmorbidity and significant financial burden on healthcare services. Despite the improvement in the outcome ofrenal transplants due to advances in diagnostic and therapeuticmethods, the role of the pathologist and the overall importanceof renal biopsy evaluation continues to be crucial. Inrecent years it has become evident that renal biopsy providesnot only the histopathological diagnosis, but is also of paramountimportance in establishing therapeutic and prognosticguidelines. The correct management of the biopsy is essentialfor an accurate diagnosis. Methods required for histopathologicalstudy of renal biopsies include routine lightmicroscopy, immunofluorescence and/or immunohistochemistry,ultrastructural evaluation and, increasingly, the use ofmolecular biology. The maximum benefit should be obtainedfrom any diagnostic test, for both scientific as well as ethicalreasons, and due to the complicities of renal pathology andthe high financial costs involved, a successful outcome canonly be achieved with efficient and experienced renal pathologists.For this reason, subspecialization in almost all branchesof pathology is increasingly becoming both an ethicalrequirement and a practical necessity. In Spain, hospitalorganization frequently results in duplication of services indifferent departments and thus many centres may examineonly small numbers of samples, making it difficult for renalpathologists to improve their experience. A joint strategy issuggested to address this problem: centralization of the interpretationof renal biopsies in centres adequately equipped for (...) (AU)

Subcutaneous ossifying fibromyxoid tumor.

Ossifying fibromyxoid tumor (OFMT) is an uncommon neoplasm occurring predominantly in the deep soft tissues of the trunk and proximal extremities. The lineage of this rare tumor to date is still uncertain. We present a case of a subcutaneous OFMT that recurred 8 years after initial resection. The histological findings of the primary and recurrent lesions are compared along with the histologic features possibly associated with aggressiveness. Dermatopathologists should consider OFMT in the differential diagnosis of subcutaneous neoplasms with a myxoid matrix.

Humoral heart rejection (severe allograft dysfunction with no signs of cellular rejection or ischemia): incidence, management, and the value of C4d for diagnosis.

Severe allograft dysfunction after heart transplant (HT), without ischemia or evidence of cellular rejection upon endomyocardial biopsy (EMB), is a rare but potentially fatal condition that suggests humoral rejection (HR). Its incidence, and the methods of choice for its diagnosis and management, remain uncertain. We retrospectively studied 445 HT patients (April 1991-December 2003) to determine incidence of HR diagnosed by clinical and conventional histopathological criteria. We used immunofluorescence (IF) techniques to test archived frozen EMB issue for IgM, IgG, C1q, C3, fibrin and C4d. Twelve patients (2.7%) fulfilled the criteria for HR after a mean time post-HT of 21.3 +/- 24.7 months (range: 2-72 months). Patients were treated with high doses of steroids and plasmapheresis, with successful recovery in 11 cases. IF studies using classical markers were mainly negative for the six patients with enough EMB tissue for testing. All six patients showed positivity for C4d during the HR episode but not before or after. Humoral rejection was observed in less than 3% of HT patients. Plasmapheresis treatment was highly effective. Classical IF tests were not useful for diagnosis, but C4d appears to be useful both for confirmation of diagnosis and for monitoring response to treatment.

Patología del trasplante renal Importancia de la biopsia en la correlación clínico-patológica / Pathology of kidney transplantation. The role of biopsy in clinicopathologic correlation

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