Overlap Syndrome of Diffuse Systemic Sclerosis, Sjögren Syndrome, and ANCA-Associated Renal-Limited Vasculitis: Three Entities in One Patient - Case Report.

Introduction: The presence of three different entities in a single patient is usually of clinical interest and mostly anecdotal. The overlap of systemic sclerosis (SSc), Sjögren syndrome (SS), and ANCA-associated renal-limited vasculitis has been reported only once previously. Case Presentation: A 61-year-old female was evaluated at consultation with 2 years of symptomatology, presenting cardboard-like skin, sclerodactyly, limited oral opening, and dry skin and eyes. She was admitted for progressive renal failure (serum creatinine, 5.5 mg/dL). Her serology work-up showed positive anti-SCL-70, anti-Ro, anti-La, anti-MPO, and antinuclear antibodies. Renal biopsy was performed and confirmed histological findings for SSc, SS, and ANCA-associated vasculitis with active extracapillary glomerulonephritis with fibrous predominance (EUVAS-Berden sclerotic class), active tubulointerstitial nephritis, focal tubular injury, and moderate chronic arteriolopathy. Treatment with 6 monthly doses of methylprednisolone and cyclophosphamide was established. At the last follow-up, the patient maintained a stable serum creatinine level of 2.6 mg/dL and had decreased proteinuria, no erythrocyturia, and no requirement for renal replacement therapy. Conclusion: Systemic sclerosis is a rare autoimmune disease; nevertheless, overlap with Sjögren syndrome is relatively common, although its association with ANCA vasculitis is anecdotal. Diagnostic integration presents a challenge for nephrologists to define the prognosis and a specific treatment.

Amiloidose renal familiar em cães da raça Shar-Pei / Family renal amyloidosis in Shar-Pei dogs / Amiloidosis renal familiar en perros Shar-Pei

A amiloidose renal familiar é uma doença incomum em cães, que afeta os rins e está associada ao acúmulo anormal de proteínas amiloides, com capacidade de promover danos orgânicos progressivos com comprometimento de funcionalidade. Caracterizada pela presença de conteúdo proteináceo glomerular, a amiloidose frequentemente está associada a quadros de falência renal, com presença de sinais clínicos variados, sendo uma condição grave e complexa. O presente artigo tem como objetivo descrever os achados clínico-laboratoriais, de imagem e histopatológicos de amiloidose familiar em dois cães da raça Shar-pei. Os animais apresentavam parentesco direto e evidenciavam sinais de cansaço, prostração e emagrecimento progressivo. As evidências clínico-laboratoriais e ultrassonográficas sugeriram a presença de glomerulonefropatia, sendo essa confirmada por exame histopatológico. Os dois cães, diante da gravidade do quadro, foram a óbito. A análise histopatológica evidenciou deposição de material proteináceo fibrilar na região glomerular e tubular, bem como infiltrado linfoplasmocítico, característicos de amiloidose renal. É essencial lembrar que a amiloidose renal familiar em cães é uma doença complexa e que as origens devem ser investigadas. O tratamento é desafiador, diante da inexistência de um manejo terapêutico definido para a doença, sendo este muitas vezes ineficaz. A empatia e o cuidado no manejo dessa condição podem ajudar a melhorar a qualidade de vida do paciente e fornecer conforto ao proprietário durante esse processo desafiador.

Family renal amyloidosis is an uncommon disease in dogs, which affects the kidneys and is associated with abnormal accumulation of amyloid proteins, capable of promoting progressive organic damage with impairment of functionality. Characterized by the presence of glomerular proteinaceous content, amyloidosis is often associated with renal failure, with the presence of varied clinical signs, being a serious and complex condition. This article aims to describe the clinical, laboratory, imaging and histopathological findings of familial amyloidosis in two Shar-pei dogs. The animals were directly related and evidenced signs of tiredness, prostration and progressive weight loss. Clinical, laboratory and ultrasonographic evidence suggested the presence of glomerulonephropathy, which was confirmed by histopathological examination. The two dogs, given the severity of the condition, died. Histopathological analysis showed deposition of fibrillar proteinaceous material in the glomerular and tubular region, as well as lymphoplasmocytic infiltrate, characteristic of renal amyloidosis. It is essential to remember that family renal amyloidosis in dogs is a complex disease and that the origins must be investigated. The treatment is challenging, given the lack of a defined therapeutic management for the disease, which is often ineffective. Empathy and care in managing this condition can help improve the patient's quality of life and provide comfort to the owner during this challenging process.

La amiloidosis renal familiar es una enfermedad poco común en perros, que afecta a los riñones y se asocia con la acumulación anormal de proteínas amiloides, con capacidad de promover daño orgánico progresivo con compromiso de la funcionalidad. Caracterizada por la presencia de contenido proteico glomerular, la amiloidosis suele asociarse a insuficiencia renal, con la presencia de signos clínicos variados, siendo una afección grave y compleja. El presente artículo tiene como objetivo describir los hallazgos clínico-laboratorios, imagenológicos e histopatológicos de la amiloidosis familiar en dos perros Sharpei. Los animales estaban directamente emparentados y presentaban signos de cansancio, postración y pérdida progresiva de peso. Los datos clínico-laboratorios y ecográficos sugirieron la presencia de glomerulonefropatía, la cual fue confirmada mediante examen histopatológico. Los dos perros, dada la gravedad del cuadro, fallecieron. El análisis histopatológico mostró depósito de material proteico fibrilar en la región glomerular y tubular, así como infiltrado linfoplasmocitario, característico de la amiloidosis renal. Es fundamental recordar que la amiloidosis renal familiar en perros es una enfermedad compleja y que es necesario investigar sus orígenes. El tratamiento es un desafío, dada la falta de un manejo terapéutico definido para la enfermedad, que muchas veces resulta ineficaz. La empatía y el cuidado en el manejo de esta afección pueden ayudar a mejorar la calidad de vida del paciente y brindar comodidad al propietario durante este desafiante proceso.

C3 glomerulopathies: dense deposit disease and C3 glomerulonephritis.

Dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are types of membranoproliferative glomerulonephritis classified as C3 glomerulopathies. These conditions are characterized by an increased number of intraglomerular cells and diffuse thickening of the glomerular capillary walls, along with the deposition of C3 and minimal or absent immunoglobulin deposits. The underlying cause of both DDD and C3Gn is an abnormal activation of the alternative complement pathway, which can result from acquired or genetic alteration. In acquired forms of DDD and C3GN, the dysregulation of the alternative pathway is commonly induced by the presence of C3 nephritic factors (C3NeFs), which are autoantibodies that stabilize C3 convertase. Both DDD and C3GN can affect individuals of any age, but DDD is primarily diagnosed in children, whereas C3GN tends to be diagnosed at a significantly higher age. The presenting features of these diseases are variable and may include proteinuria, hematuria, hypertension, or kidney failure. A common finding in these diseases is low serum C3 levels with normal serum C4 levels. Chronic deterioration of renal function is commonly observed in DDD and C3GN, often leading to end-stage renal disease (ESRD), especially in DDD. Kidney transplantation outcomes in patients with these conditions are characterized by histological recurrence, which may contribute to higher rates of allograft failure.

The correlation of spot urinary protein-to-creatinine ratio with 24-h urinary protein excretion in various glomerulopathies.

BACKGROUND: Proteinuria is an important and well-known biomarker of many forms of kidney injury. Its quantitation is of particular importance in the diagnosis and management of glomerular diseases. Its quantification can be done by several methods. Among these, the measurement of 24-h urinary protein excretion is the gold standard method. However, it is cumbersome, time-consuming, and inconvenient for patients and is not completely foolproof. Many alternative methods have been tested over time albeit with conflicting results. Among the latter, the measurement of urine protein-to-creatinine ratio (uPCR) in single-voided urinary samples is widely used. The majority of studies found a good correlation between uPCR in single urine samples with 24-h urinary protein estimation, whereas others did not. AIM: To investigate the correlation of spot uPCR with 24-h urinary protein estimation in patients suffering from different forms of glomerulopathies at a single large-volume nephrological center in Pakistan. METHODS: This cross-sectional, observational study was conducted at the Department of Nephrology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan from September 2017 to March 2018. All newly presenting adult patients with proteinuria who were being investigated for suspected glomerulonephritis and persistent proteinuria with ages between 18 to 60 years were enrolled. All patients were given detailed advice regarding 24-h urine collection starting at 7:00 AM for total protein and creatinine excretion estimations. A spot urine sample was collected the next day at the time of submission of a 24-h urine sample for measuring uPCR along with a blood sample. The data of patients were collected in a proforma. SPSS version 20.0 was used for statistical analysis. RESULTS: A total of 157 patients were included. Their mean age was 30.45 ± 12.11 years. There were 94 (59.8%) males and 63 (40.2%) females. The mean 24-h urinary protein excretion was 3192.78 ± 1959.79 mg and the mean spot uPCR was 3.16 ± 1.52 in all patients. A weak but significant correlation was observed between spot uPCR and 24-h urinary protein excretion (r = 0.342, P = 0.01) among all patients. On subgroup analysis, a slightly better correlation was found in patients older than 47 years (r = 0.78), and those with body mass index > 25 kg/m2 (r = 0.45). The Bland and Altman's plot analysis comparing the differences between spot uPCR and 24-h protein measurement also showed a wide range of the limits of agreement between the two methods. CONCLUSION: Overall, the results from this study showed a significant and weakly positive correlation between spot uPCR and 24-h urinary protein estimation in different forms of glomerulopathies. The agreement between the two methods was also poor. Hence, there is a need for careful interpretation of the ratio in an unselected group of patients with kidney disease.

Patrones morfológicos de la enfermedad glomerular en México: Reporte de un centro de referencia en nefropatología / Morphological patterns of glomerular disease in Mexico: Report of a reference center in nephropathology

RESUMEN Introducción: En México, la enfermedad renal crónica (ERC) representa un gran problema de salud y las glomerulopatías (GP) representan la tercera causa de ERC. Objetivo: Describir, desde una base de datos de biopsias renales (BR) nativas, los diferentes patrones morfológicos de GP en México. Métodos: Se analizaron registros de BR de riñón nativo en un centro de referencia en nefropatología, todas las BR fueron evaluadas por una única nefropatóloga (AVP). El diagnóstico final en cada caso se basó en parámetros clínicos e histopatológicos. Resultados: Fueron revisadas 2084 BR, con edad de 34.4 ± 17.6 años. 1085 BR (52.1%) en género femenino; el síndrome nefrótico fue más frecuente en hombres (p<0.001) y síndrome nefrítico fue más frecuente en mujeres (p<0.001). GP primarias y nefropatías túbulo-intersticiales fueron más diagnosticadas en hombres (p<0.01). Nefritis lúpica (NL) fue la GP secundaria más reportada. La glomeruloesclerosis focal y segmentaria (GEFS) fue la GP primaria diagnosticada con mayor frecuencia en ambos géneros. Vasculitis por inmunoglobulina A fue la enfermedad vascular más frecuentemente detectada. Síndrome nefrótico fue la indicación más frecuente de BR (42.9%), seguido de: síndrome nefrítico (23.9%), proteinuria aislada (16.4%), daño renal agudo (8.7%), alteraciones urinarias asintomáticas (6.2%) y ERC (1.8%). Conclusiones: La GP primarias con mayor frecuencia fueron GEFS. Las GP secundarias más frecuentemente reportadas fueron NL, predominantemente en mujeres. Se observó nefropatía IgA con mayor frecuencia en comparación con otras series publicadas en México. Hubo diferencias significativas en la presentación de GP en relación con el género y la edad del paciente.

ABSTRACT Introduction: In Mexico, chronic kidney disease (CKD) represents a major health problem, and glomerulopathies (GP) represent the third leading cause of CKD. Aim: From a database of native kidney biopsies (KB), describe the different morphological patterns of GP in Mexico. Methods: Records of native KB in a nephropathology referral center were evaluated by a single nephropathologist. The final diagnosis in each case was based on clinical parameters and histopathological findings. Results: 2084 KB were analyzed, patients were 34.4±17.6 years of age, there were 1085 KB (52.1%) in females; nephrotic syndrome was most frequent in males (p<0.001), and nephritic syndrome was more frequent in females (p <0.001). Primary GP and túbulo-interstitial diseases were most diagnosed in males (p <0.01). Lupus nephritis (LN) was the most-reported secondary GP. Focal and segmental glomerulosclerosis (FSGS) was the primary GP most often diagnosed in both genders. The most frequently detected vascular disease was immunoglobulin A vasculitis. Nephrotic syndrome was the most frequent indication for KB (42.9%), followed by: nephritic syndrome (23.9%), isolated proteinuria (16.4%), acute kidney injury (8.7%), asymptomatic urinary alterations (6.2%), and CKD (1.8%). Conclusions: The most frequently observed primary GP was FSGS, and LN was the most frequent secondary GP, predominantly in females, and IgA nephropathy was observed more frequently in comparison with other series published in Mexico. There were significant differences in GP presentation in relation to patient sex and age.

Kidney biopsy during pregnancy: a difficult decision. A case series reporting on 20 patients from Mexico.

BACKGROUND: Kidney biopsy is a routine procedure in the diagnosis of kidney disease, but during pregnancy it carries potential adverse effects for both mother and child, aside from the challenges of obtaining adequate tissue samples. Nevertheless, a precise diagnosis is necessary when specific and potentially toxic treatments are to be used during pregnancy. The present report presents our experience with regard to the usefulness and safety of kidney biopsies during pregnancy. METHODS: Retrospective analysis of clinical indications, complications, histopathological diagnoses, and treatment of patients who had kidney biopsies done at a single academic center during gestation weeks 11-30 between January 2015 and January 2019. RESULTS: Kidney biopsies were carried out in 20 pregnant patients with nephrotic proteinuria. Biopsy was adequate in all patients. The histological diagnoses included focal segmental glomerulosclerosis (collapsing, tip and perihiliar varieties), membranous lupus nephropathy, diabetic nephropathy, and IgA nephropathy. Treatment was associated with reduction of proteinuria in 17 patients and reduction of serum creatinine in 9 out of 11 patients who had serum creatinine ≥ 1 mg/dl at the time of biopsy. There was one major bleeding complication that required transfusion of one unit of blood. There was a high incidence of preeclampsia, preterm delivery, and low birth weight despite appropriate kidney disease therapy. CONCLUSIONS: Kidney biopsy may be done during pregnancy when therapeutic decisions depend on a precise pathologic diagnosis.

Glomerulopatía por C3: algoritmo diagnóstico en gestantes

La enfermedad glomerular comprende un grupo heterogéneo de entidades que se caracterizan por la pérdida de la arquitectura o función del glomérulo secundario a proceso inflamatorio del mismo de etiología autoinmune, infecciosa, paraneoplásica, que puede ser identificada con estudios de histopatología. Su reconocimiento durante la gestación representa un reto diagnóstico por la sobreposición de cambios fisiológicos, el debut de enfermedades autoinmunitarias o de enfermedades genéticas, entre otros. La presentación clínica suele encajar en grupos sindromáticos específicos, sin embargo, es frecuente que sean clínicamente indistinguibles o sobrepuestos. El debut de la enfermedad renal con curso clínico de rápida instauración y de evolución desfavorable con respecto a la función renal, hace mandatorio un estudio completo desde el abordaje clínico hasta la interpretación de los hallazgos histopatológicos, encaminado en la distinción de causas primarias y secundarias. Si bien las glomerulonefritis primarias no son las más frecuentes en la gestación, la identificación certera del diagnóstico y su adecuada clasificación permite el manejo dirigido y óptimo de las mismas. Se presentan los casos clínicos de dos gestantes con enfermedad glomerular primaria, con discrepancia en su diagnóstico, enfatizando en sus manifestaciones durante el curso de la gestación, el algoritmo diagnóstico utilizado, el tratamiento inicial y de mantenimiento utilizado. Se resalta la utilidad de la biopsia renal, específicamente la inmunofluorencia para aclarar el mismo.

Glomerular disease involves a heterogeneous group of entities that are characterized by loss of the architecture and function of the glomerulus and this can be caused by immunity, infectious and paraneoplastic etiologies. The aforementioned can be identified in histopathological studies. The recognition of this entity during pregnancy represents a diagnostic challenge due to the superposition of physiological changes, the development of autoimmune diseases and / or genetic disease, among others. Clinical manifestations can be into specific syndromic groups; however we can find indistinguishable manifestations and overlapping of this. When the disease is present its common to find rapidly establishment and unfavorable evolution about renal function. With this it's necessary to complete studies involving the initial clinical approach until histopathological findings with the goal to find primary and secondary causes. As it's known primary glomerulonephritis is not the most frequent in pregnancy, the accuracy in the diagnosis and the proper classification allows the direct and soon management. In this case report we describe 2 pregnant women with primary glomerular disease with discrepancy in their diagnosis. We talk about manifestations during pregnancy, the algorithm used in the diagnosis and finally the initial treatment and the maintenance used in these patients.

New Onset Biopsy-Proven Nephropathies after COVID Vaccination.

INTRODUCTION: To date, almost 7 billion doses of the different types of vaccine against SARS-CoV-2 have been administered worldwide. Although the severity of new cases of SARS-CoV-2 has progressively decreased, and the pressure on national health systems has declined, the development of de novo glomerular injuries has been suggested. METHODS: This study aimed to examine the patients who were hospitalized in our Unit between April and November 2021 and underwent renal biopsy for new-onset urinary abnormalities (UA) and/or renal impairment within 3 months of SARS-CoV-2 vaccination. RESULTS: We identified 17 patients who developed UA and/or renal insufficiency within 3 months of vaccination. Minimal change disease was the most common disease in our cohort (5 patients, 29.4%) followed by acute tubulointerstitial nephritis (TIN; 3 patients, 17.6%), membranous nephropathy (3 patients, 17.6%), and rapidly progressive IgA nephropathy (2 patients, 11.8%). The other 4 patients had a diagnosis of membranoproliferative glomerulonephritis (1 patient), systemic lupus erythematosus (1 patient), ANCA-associated vasculitis (1 patient), and tip-variant focal segmental glomerulosclerosis (1 patient), respectively. Eight out of the 17 patients (47.1%) developed acute kidney injury. Two patients with acute TIN had to start hemodialysis that was discontinued after 1 and 2 months, respectively, due to the recovery of renal function. All patients underwent treatment with corticosteroids and/or immunosuppressants. DISCUSSION: Although it is not possible to conclusively determine whether there is a causal relationship between SARS-CoV-2 vaccination and new-onset nephropathies, based on the appearance of UA and/or renal insufficiency shortly after vaccination, we hypothesize that the immune response to the COVID-19 vaccine may be a trigger of nephropathies. Therefore, our results highlight the need for pharmacovigilance. However, this report should not lead to vaccine hesitation during this pandemic as the benefits of vaccination strongly outweigh the potential risks.

Relapsing minimal change disease superimposed on late-onset p.N215S Fabry nephropathy.

We present the case of a 76-year-old man with late-onset Fabry disease caused by the p.N215S missense mutation, with Fabry cardiomyopathy and nephropathy. In this case, the diagnosis of Fabry disease was incidental and followed minimal change disease (MCD) onset, with nephrotic syndrome and acute kidney injury requiring renal replacement therapy. Fabry nephropathy associated with the p.N215S mutation is becoming increasingly recognized among older patients. The importance of electron microscopy is herein highlighted and histological features common to Fabry nephropathy and MCD are discussed, along with the challenges associated with the diagnosis and clinical management.

Modeling C3 glomerulopathies: C3 convertase regulation on an extracellular matrix surface.

Introduction: C3 glomerulopathies (C3G) are ultra-rare complement-mediated diseases that lead to end-stage renal disease (ESRD) within 10 years of diagnosis in ~50% of patients. Overactivation of the alternative pathway (AP) of complement in the fluid phase and on the surface of the glomerular endothelial glycomatrix is the underlying cause of C3G. Although there are animal models for C3G that focus on genetic drivers of disease, in vivo studies of the impact of acquired drivers are not yet possible. Methods: Here we present an in vitro model of AP activation and regulation on a glycomatrix surface. We use an extracellular matrix substitute (MaxGel) as a base upon which we reconstitute AP C3 convertase. We validated this method using properdin and Factor H (FH) and then assessed the effects of genetic and acquired drivers of C3G on C3 convertase. Results: We show that C3 convertase readily forms on MaxGel and that this formation was positively regulated by properdin and negatively regulated by FH. Additionally, Factor B (FB) and FH mutants impaired complement regulation when compared to wild type counterparts. We also show the effects of C3 nephritic factors (C3Nefs) on convertase stability over time and provide evidence for a novel mechanism of C3Nef-mediated C3G pathogenesis. Discussion: We conclude that this ECM-based model of C3G offers a replicable method by which to evaluate the variable activity of the complement system in C3G, thereby offering an improved understanding of the different factors driving this disease process.

Substitutions at position 263 within the von Willebrand factor type A domain determine the functionality of complement C2 protein.

The complement system is one of the first defense lines protecting from invading pathogens. However, it may turn offensive to the body's own cells and tissues when deregulated by the presence of rare genetic variants that impair physiological regulation and/or provoke abnormal activity of key enzymatic components. Factor B and complement C2 are examples of paralogs engaged in the alternative and classical/lectin complement pathway, respectively. Pathogenic mutations in the von Willebrand factor A domain (vWA) of FB have been known for years. Despite substantial homology between two proteins and the demonstration that certain substitutions in FB translated to C2 result in analogous phenotype, there was a limited number of reports on pathogenic C2 variants in patients. Recently, we studied a cohort of patients suffering from rare kidney diseases and confirmed the existence of two gain-of-function and three loss-of-function mutations within the C2 gene sequences coding for the vWA domain (amino acids 254-452) or nearly located unstructured region (243-253) of C2 protein. Herein, we report the functional consequences of amino acid substitution of glutamine at position 263. The p.Q263G variant resulted in the gain-of-function phenotype, similarly to a homologous mutation p.D279G in FB. Conversely, the p.Q263P variant found in a patient with C3 glomerulopathy resulted in the loss of C2 function. Our results confirm that the N-terminal part of the vWA domain is a hot spot crucial for the complement C2 function.

The spectrum of biopsy-proven glomerular diseases in a tertiary Hospital in Southern Brazil.

BACKGROUND: The prevalence and distribution of glomerular diseases differ among countries, and the indication to perform a kidney biopsy varies among centres. In this study, we assessed the prevalence of primary and secondary glomerulopathies based on histological diagnoses, and the correlation between glomerulopathies and demographic and clinical data was evaluated. METHODS: In this study, 1051 kidney biopsies were retrospectively reviewed between 2000 and 2018. Patient demographic, clinical and laboratory data were assessed. The prevalence of primary glomerulonephritis (PG) and secondary glomerulopathies (SG), as well as tubulointerstitial diseases (TIDs), hereditary nephropathies (HNs) and other diagnoses, were determined. The frequency of primary and secondary glomerulopathies was evaluated by age group, and the temporal variation in frequencies across three time periods (2000-2005, 2006-2011, and 2012-2018) was reported. RESULTS: The prevalence of SG predominated (52.4%), followed by PG (29.6%), other diagnoses (10.7%), TID (6.6%) and HN (1.1%). Among the primary forms of glomerular disease, focal segmental glomerulosclerosis (FSGS) was the most common (37.3%), followed by IgA nephropathy (IgAN, 24.4%), membranous nephropathy (MN, 18.6%) and minimal change disease (MCD, 8.4%). Lupus nephritis (LN, 41.1%) was most common in patients with SG, followed by diabetic kidney disease (DKD, 17.8%), systemic vasculitis (SV, 10.2%) and secondary FSGS (2nd FSGS, 10%). Nephrotic syndrome was the most common clinical presentation in patients with PG and also in patients with DRD and 2nd FSGS, whereas in patients with IgAN and SV, nephritic syndrome was the main presentation. For the age group between 18 and 50 years, LN, FSGS and IgAN predominated; for patients aged between 51 and 65 years, the proportion of DKD and 2nd FSGS increased, and SV was more common in patients > 65 years. The temporal variation in PG across the three time periods showed a statistically significant increase in IgAN (p = 0.001) and a reduction in FSGS over time (p < 0.001). In SG, there was a reduction in LN (p = 0.027) and an increase in DKD (p < 0.001) over time, with a tendency for 2nd FSGS to decrease over time (p = 0.053). CONCLUSIONS: In the studied kidney biopsy registry, FSGS and IgAN were the most prevalent diagnoses in patients with PG, and LN and DKD were the most prevalent in patients with SG. Nephrotic syndrome was the major indication for biopsy. When comparing the temporal variation in glomerulopathies, there was a reduction in FSGS and an increase in IgAN in patients with PGs over time, and for patients with SGs, there was a reduction in LN with an increase in cases of DKD over time.

Thrombotic Microangiopathy, an Unusual Form of Monoclonal Gammopathy of Renal Significance: Report of 3 Cases and Literature Review.

Monoclonal gammopathies result from neoplastic clones of the B-cell lineage and may cause kidney disease by various mechanisms. When the underlying clone does not meet criteria for a malignancy requiring treatment, the paraprotein is called a monoclonal gammopathy of renal significance (MGRS). One rarely reported kidney lesion associated with benign paraproteins is thrombotic microangiopathy (TMA), provisionally considered as a combination signifying MGRS. Such cases may lack systemic features of TMA, such as a microangiopathic hemolytic anemia, and the disease may be kidney limited. There is no direct deposition of the paraprotein in the kidney, and the presumed mechanism is disordered complement regulation. We report three cases of kidney limited TMA associated with benign paraproteins that had no other detectable cause for the TMA, representing cases of MGRS. Two of the cases are receiving clone directed therapy, and none are receiving eculizumab. We discuss in detail the pathophysiological basis for this possible association. Our approach to therapy involves first ruling out other causes of TMA as well as an underlying B-cell malignancy that would necessitate direct treatment. Otherwise, clone directed therapy should be considered. If refractory to such therapy or the disease is severe and multisystemic, C5 inhibition (eculizumab or ravulizumab) may be indicated as well.

Recurrent Glomerular Diseases in Renal Transplantation with Focus on Role of Electron Microscopy.

Background: The common causes of renal transplant complications include active or chronic rejection process, infections, and toxicity but also recurrent or de novo diseases, which play an important role in affecting long-term graft function or graft loss. Summary: Recurrent disease in renal transplantation is defined as recurrence of the original kidney disease leading to end-stage kidney disease. They comprise a heterogeneous group of predominantly glomerular and some tubulointerstitial and vascular lesions, which include primary kidney diseases (e.g., focal segmental glomerulosclerosis, membranous glomerulonephritis, and IgA nephropathy) or those secondary to systemic autoimmune, metabolic, and infectious processes that can range from subclinical to clinically overt acute, subacute, or chronic clinical presentations. In addition to the knowledge of prior renal disease and routine/periodic serum and urine testing for kidney function, a complete transplant renal biopsy examination is essential in the identification and differentiation of these diseases. The time of onset and severity of these diseases depend on the underlying etiopathogenetic mechanisms and the varied rates of recurrence in the early or late posttransplant period, often being modified by the current immunosuppressive protocols and other donor and recipient predisposing characteristics. Key Messages: Transplant kidney biopsy findings provide diagnostic accuracy and prognostic information regarding the potential for reversibility along with detection of unsuspected or clinically symptomatic recurrent diseases, with any concomitant rejection process or toxicity, for appropriate therapeutic decision-making. Routine electron microscopy in transplant kidney biopsies is a valuable tool in recognizing fully developed or early/subtle features of evolving recurrent diseases, often during the subclinical phases, in for cause or surveillance allograft biopsies.

Gangliosides in Podocyte Biology and Disease.

Gangliosides constitute a subgroup of glycosphingolipids characterized by the presence of sialic acid residues in their structure. As constituents of cellular membranes, in particular of raft microdomains, they exert multiple functions, some of them capital in cell homeostasis. Their presence in cells is tightly regulated by a balanced expression and function of the enzymes responsible for their biosynthesis, ganglioside synthases, and their degradation, glycosidases. The dysregulation of their abundance results in rare and common diseases. In this review, we make a point on the relevance of gangliosides and some of their metabolic precursors, such as ceramides, in the function of podocytes, the main cellular component of the glomerular filtration barrier, as well as their implications in podocytopathies. The results presented in this review suggest the pertinence of clinical lipidomic studies targeting these metabolites.

Substitution of Oral for Intravenous Cyclophosphamide in Membranous Nephropathy.

Background: Optimal immunosuppressive treatment for membranous nephropathy is still a matter of controversy. Current recommendations include oral cyclophosphamide combined with steroids (modified Ponticelli regimen) as first-line treatment in patients who are high risk. However, concerns about the cumulative toxicity of oral cyclophosphamide persist. In the last 30 years, a protocol based on low-dose intravenous cyclophosphamide plus steroids has been used to treat membranous nephropathy in Uruguay. We aimed to assess the efficacy of this regimen to induce clinical remission in patients with membranous nephropathy. Methods: In this retrospective, observational cohort study, we analyzed the outcome of 55 patients with membranous nephropathy treated between 1990 and 2017 with a 6-month course of alternating steroids (months 1, 3, and 5) plus intravenous cyclophosphamide (single dose of 15 mg/kg on the first day of months 2, 4, and 6). Results: At 24 months, 39 (71%) patients achieved clinical response with complete remission observed in 23 patients (42%) and partial remission in 16 (29%). Median time to achieve partial and complete remission was 5.9 and 11.5 months, respectively. Absence of response was observed in 16 patients (29%), five of whom started chronic RRT after a median follow-up of 3.5 years. Clinical relapse occurred in nine of 33 (27%) patients at a median of 34 months after treatment discontinuation. Conclusions: Replacement of oral cyclophosphamide with a single intravenous pulse on months 2, 4, and 6 of the modified Ponticelli regimen can be an effective and safe alternative for treatment of membranous nephropathy. Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/K360/2020_09_24_KID0002802020.mp3.

Inherited glomerular diseases in the gilded age of genomic advancements.

The synchronized advent of high-throughput next-generation sequencing technology and knowledge of the human genome has rendered exponential contributions to our understanding of the pathophysiology of glomerular kidney diseases. A genetic diagnosis can now be made or confirmed in about two-thirds of the suspected inherited glomerular diseases. Next-generation sequencing is adept at identifying single nucleotide variations and small insertions or deletions that constitute majority of the disease-causing mutations. Description of the complete mutation spectrum in syndromic glomerulopathies may require the use of both sequencing and cytogenetic methods to detect large structural DNA variation in addition to single nucleotide changes. The enthusiastic application of genetic and genomic knowledge to inherited glomerular diseases has uncovered anticipated and unforeseen challenges mainly related to the biological interpretation of variants of uncertain significance and the limited benefit on clinical management for the individual patient when a diagnosis is obtained. To attain the ultimate goal of transforming clinical decision-making based on accurate genetic diagnosis using genomic information, these challenges need to be addressed. Till then, the glory of genomic medicine stands the test of time in this gilded age of genomic advancements.

[Ultrastructural study of podocyte alterations in non proliferative glomerulopathy]. / Ul'trastrukturnoe issledovanie al'teratsii podotsitov pri neproliferativnykh glomerulopatiiakh.

Ultrastructural changes in podocytes are an important diagnostic and prognostic marker for nephropathies. However, the biomedical understanding of detected submicroscopic changes in podocytes remains controversial. OBJECTIVE: To investigate the relationship between the ultrastructural changes of podocytes (fusion of cytopodia and denudation of the basement membrane as a result of their desquamation) with a number of clinical and laboratory indicators of kidney dysfunction in case of non-proliferative glomerulopathies (NPGP). Thirty-seven patients (23 men, 14 women) with NPGP, including 8 with focal segmental glomerulosclerosis (FSGS), 17 with membranous nephropathy (MN), and 12 with minimal change disease (MCD), were examined. SUBJECT AND METHODS: All the patients underwent standard laboratory and instrumental studies: determinations of the levels of total serum cholesterol (mmol/l), total serum protein (g/l); serum albumin (g/l); CKD-EPI glomerular filtration rate (GFR) (ml/min/1.73 m2), and daily protein loss (g/day). Light optical changes were measured; completely sclerotic and/or focally segmentally sclerotic glomeruli were taken into account. Quantitative ultrastructural stereological analysis was carried out estimating the cytopodium width (CPW) and the degree of glomerular basement membrane denudation (GBMD) (%). RESULTS: NPGP cases showed the largest number of sclerotic glomeruli in FSGS, which was accompanied by the lowest level of daily proteinuria and GFR. Quantitative values of CPW were associated with the level of daily protein loss (r=0.47; p < 0.05) and serum albumin (r=-0.57; p <0.05) in patients with nephrotic syndrome. In MN, the absolute value of CPW was larger than that in the other two patient groups. A correlation analysis of CPW and GBMD values among patients with NPGP revealed a statistically insignificant negative relation between these morphometric parameters. However, when a subgroup of patients with podocytopathies (only MCD and FSGS) was identified in the study group, this relationship was found to be significant (r=-0.54; p=0.012). CONCLUSION: The patients with NPGP exhibited a relationship between the severity of nephrotic syndrome and proteinuria/hypoalbuminemia, on the one hand, and CPW, on the other. The established negative relationship between CPW and the percentage of GBMD in the subgroup of patients with podocytopathies may be due to the early stages of podocyte injury, which are accompanied by transient GBMD.

Kidney Lipidomics by Mass Spectrometry Imaging: A Focus on the Glomerulus.

Lipid disorders have been associated with glomerulopathies, a distinct type of renal pathologies, such as nephrotic syndrome. Global analyses targeting kidney lipids in this pathophysiologic context have been extensively performed, but most often regardless of the architectural and functional complexity of the kidney. The new developments in mass spectrometry imaging technologies have opened a promising field in localized lipidomic studies focused on this organ. In this article, we revisit the main works having employed the Matrix Assisted Laser Desorption Ionization Time of Flight (MALDI-TOF) technology, and the few reports on the use of TOF-Secondary Ion Mass Spectrometry (TOF-SIMS). We also present a first analysis of mouse kidney cortex sections by cluster TOF-SIMS. The latter represents a good option for high resolution lipid imaging when frozen unfixed histological samples are available. The advantages and drawbacks of this developing field are discussed.

Factor B and C4b2a Autoantibodies in C3 Glomerulopathy.

C3 Glomerulopathy (C3G) is a renal disease mediated primarily by dysregulation of the alternative pathway of complement. Complement is the cornerstone of innate immunity. It targets infectious microbes for destruction, clears immune complexes, and apoptotic cells from the circulation, and augments the humoral response. In C3G, this process becomes dysregulated, which leads to the deposition of complement proteins-including complement component C3-in the glomerular basement membrane of the kidney. Events that trigger complement are typically environmental insults like infections. Once triggered, in patients who develop C3G, complement activity is sustained by a variety of factors, including rare or novel genetic variants in complement genes and autoantibodies that alter normal complement protein function and/or regulation. Herein, we review two such autoantibodies, one to Factor B and the other to C4b2a, the C3 convertase of the classical, and lectin pathways. These two types of autoantibodies are identified in a small fraction of C3G patients and contribute marginally to the C3G phenotype.