Nefropatía por IgA con microangiopatía trombótica / IgA nephropathy with thrombotic microangiopathy

INTRODUCTION: IgA nephropathy is the most common glomerulopathy in the world, it has a wide clinical expression, from asymptomatic to rapidly progressive glomerulonephritis. The definitive diagnosis is renal biopsy, within which the IgA pattern can be identified, including thrombotic microangiopathy. CLINICAL CASE: 28-year-old female patient, with a history of preeclampsia in the last pregnancy, presents high blood pressure, hematuria and proteinuria. Study begins with initially negative results. Renal biopsy confirms IgA nephropathy with thrombotic microangiopathy. DISCUSSION: Vascular damage is underestimated in IgA nephropathy. Thrombotic microangiopathy can be associated with various clinical manifestations, however when it is associated with IgA Nephropathy it is usually associated with proteinuria, arterial hypertension and elevation of creatinine. In the presence of microangiopathy, secondary causes must be ruled out. In general, there is no pathognomonic serological marker. Eventually patients could benefit from the use of eculizumab. CONCLUSION: IgA nephropathy is the most common glomerulopathy worldwide; there is a wide range of clinical presentations, among which thrombotic microangiopathy can be found. This presentation is associated with a higher risk of progression to end-stage renal disease.

INTRODUCCIÓN: La nefropatía por IgA es la glomerulopatía más frecuente en el mundo, tiene una amplia expresión clínica, desde asintomática hasta glomerulonefritis rápidamente progresivas. El diagnóstico definitivo es la biopsia renal, dentro de las cuales se puede identificar el patrón de la IgA, dentro de los cuales está la microangiopatía trombótica. CASO CLÍNICO: Paciente femenina 28 años, con antecedentes de preeclampsia en último embarazo, presenta hipertensión arterial, hematuria y proteinuria. Se inicia estudio con resultados inicialmente negativos. Biopsia renal confirma nefropatía por IgA con microangiopatía trombótica. DISCUSIÓN: En la nefropatía por IgA se subestima el daño vascular. La microangiopatía trombótica se puede asociar con varias manifestaciones clínicas, sin embargo, cuando está asociada a NIgA suele estar asociado con proteinuria, hipertensión arterial y elevación y creatinina. Ante la presencia de microangiopatía, se deben descartar causas secundarias de la misma. En general no existe un marcador serológico patognomónico. Eventualmente los pacientes se podrían beneficiar del uso de eculizumab. CONCLUSIÓN: La nefropatía por IgA es la glomerulopatía más frecuente a nivel mundial, existe una gran gama de presentaciones clínicas, dentro de las cuales se puede encontrar microangiopatía trombótica. Esta última presentación se asocia con mayor riesgo de progresión a enfermedad renal en etapa terminal.

Thrombomodulin Gene Mutation and Associated Predisposing Factors in Familial Collapsing Glomerulopathy.

Collapsing glomerulopathy (CG) is a rare glomerular disease and its familial form is even rarer. CG and non-collapsing forms of focal segmental glomerulosclerosis may both be caused by pathogenic variants in the same genes, but there is less information on genetics of the former disease. We hypothesized that different hits (viral infection and genetic variants) may be involved in the development of a familial CG here described. We performed renal and etiological routine evaluation, PVB19 serology, genetic tests including whole-exome analysis and dosage of serum thrombomodulin (THBD) in two siblings with CG, one healthy sister, and their mother. The THBD gene variant p.A43T in homozygosity was identified in the proband and her affected brother, both with CG. The same mutation was identified in their mother in heterozygosity. THBD levels were elevated in the serum of both affected siblings. They also had PVB19 positive serology and the G1 high-risk apolipoprotein L1 (APOL1) alleles in homozygosity. Their healthy sister had no PVB19-positive serology and no THBD nor APOL1 gene variants. In this case of familial CG, THBD, and APOL1 gene variants, and a previous PVB19 infection may be associated with the development of CG in a multihit process. In addition, the p.A43T THBD variant, identified in the affected siblings, has never been previously described in homozygosis, pointing to a likely autosomal recessive CG trait caused by this gene mutation.

Idiopathic collapsing glomerulopathy is associated with APOL1 high-risk genotypes or Mendelian variants in most affected individuals in a highly admixed population.

Collapsing glomerulopathy (CG) is most often associated with fast progression to kidney failure with an incidence apparently higher in Brazil than in other countries. However, the reason for this occurrence is unknown. To better understand this, we performed an integrated analysis of clinical, histological, therapeutic, causative genetic and genetic ancestry data in a highly genetically admixed cohort of 70 children and adult patients with idiopathic CG (ICG). The disease onset occurred at 23 (interquartile range: 17-31) years and approximately half of patients progressed to chronic kidney disease requiring kidney replacement therapy (CKD-KRT) 36 months after diagnosis. Causative genetic bases, assessed by targeted-gene panel or whole-exome sequencing, were identified in 58.6% of patients. Among these cases, 80.5% harbored APOL1 high-risk genotypes (HRG) and 19.5% causative Mendelian variants (MV). Self-reported non-White patients more frequently had HRG. MV was an independent risk factor for progression to CKD-KRT by 36 months and the end of follow-up, while remission was an independent protective factor. All patients with HRG manifested CG at 9-44 years of age, whereas in those with APOL1 low-risk genotype, the disease arose throughout life. HRGs were associated with higher proportion of African genetic ancestry. Novel causative MVs were identified in COL4A5, COQ2 and PLCE1 and previously described causative MVs were identified in MYH9, TRPC6, COQ2, COL4A3 and TTC21B. Three patients displayed HRG combined with a variant of uncertain significance (ITGB4, LAMA5 or PTPRO). MVs were associated with worse kidney prognosis. Thus, our data reveal that the genetic status plays a major role in ICG pathogenesis, accounting for more than half of cases in a highly admixed Brazilian population.

German Shorthaired Pointer dogs with exfoliative cutaneous lupus erythematosus develop immune-complex membranous glomerulonephropathy.

German Shorthaired Pointer (GSHP) dogs with a UNC93B1 gene mutation develop exfoliative cutaneous lupus erythematosus (ECLE) and kidney disease resembling lupus nephritis in humans. The objective of this study was to characterize the kidney disease by light microscopy, immunofluorescence, and electron microscopy in a population of GSHP dogs with ECLE. Medical records were reviewed, and light microscopy of kidneys from 7 GSHP dogs with a previous histologic diagnosis of ECLE was performed. Immunofluorescence of fresh-frozen kidney from 1 dog and transmission electron microscopy of kidney from that dog and 2 additional dogs were performed. Five of 7 dogs had proteinuria diagnosed by urinalysis or urine protein-to-creatinine ratio. Two of 7 dogs were intermittently hypoalbuminemic, and none were azotemic. Histologic findings included early (2 dogs) to late (5 dogs) membranous glomerulonephropathy characterized by mild-to-severe glomerular capillary loop thickening and tubular proteinosis. In all 7 cases, trichrome staining revealed red granular immune deposits on the subepithelial surface of the glomerular basement membrane. Immunofluorescence revealed strong granular labeling for immunoglobulins and complement protein C3. Electron microscopy demonstrated subepithelial electron-dense immune deposits encircled by the remodeled glomerular basement membrane. These findings are diagnostic of immune-complex membranous glomerulonephropathy and are similar to class V lupus in humans. This cohort of GSHP dogs with ECLE developed immune-complex membranous glomerulonephropathy, which we hypothesize is a manifestation of systemic lupus erythematosus. GSHP dogs with ECLE should undergo clinical evaluation of renal function for early identification and treatment.

Collapsing Glomerulopathy: A Review by the Collapsing Brazilian Consortium.

Collapsing glomerulopathy (CG) is a clinicopathologic entity characterized by segmentar or global collapse of the glomerulus and hypertrophy and hyperplasia of podocytes. The Columbia classification of 2004 classified CG as a histological subtype of focal segmental glomerulosclerosis (FSGS). A growing number of studies have demonstrated a high prevalence of CG in many countries, especially among populations with a higher proportion of people with African descent. The present study is a narrative review of articles extracted from PubMed, Medline, and Scielo databases from September 1, 2020 to December 31, 2021. We have focused on populational studies (specially cross-sectional and cohort articles). CG is defined as a podocytopathy with a distinct pathogenesis characterized by strong podocyte proliferative activity. The most significant risk factors for CG include APOL1 gene mutations and infections with human immunodeficiency virus and severe acute respiratory syndrome coronavirus 2. CG typically presents with more severe symptoms and greater renal damage. The prognosis is notably worse than that of other FSGS subtypes.

Chikungunya virus as a trigger for different renal disorders: an exploratory study.

INTRODUCTION: Chikungunya virus was detected in cases of acute chikungunya fever in renal tissue. However, chikungunya virus-related kidney injury still lacks characterization, and it is unknown whether the kidneys are reservoirs for the virus. We sought to detect histopathological changes and viral antigens in renal tissue, and to evaluate kidney injury markers in different phases of chikungunya fever. METHODS: Two groups were evaluated in this exploratory study: patients with biopsy-proven kidney injury established after chikungunya fever, and patients with post-chikungunya fever chronic joint manifestations without known kidney injury, in whom we actively searched for kidney injury markers. RESULTS: In the first group, 15 patients had kidney injury 0.5-24 months after chikungunya fever. The most frequent histopathological diagnoses were glomerular lesions. No viral antigens were detected in renal tissue. High-risk genotypes were detected in patients with atypical hemolytic uremic syndrome and focal and segmental glomerulosclerosis. In the second group, 114 patients had post-chikungunya fever joint manifestations on average for 35.6 months. Mean creatinine and proteinuria were 0.9 mg/dl and 71.5 mg/day, respectively. One patient had isolated hematuria. There was no indication for renal biopsy in this group. CONCLUSIONS: Several histopathological features were found after chikungunya fever, without virus detection in renal tissue. These findings suggest that chikungunya virus may trigger kidney lesions with varying degrees of severity at different stages of infection. However, the probability that this virus replicates in the renal tissue seems unlikely.

Jornadas del Comité de Nefropatía de la Sociedad Argentina de Diabetes. Actualización de cirugía bariátrica en paciente con diabetes y enfermedad renal. Parte 2 / Conference of the Nephropathy Committee of the Argentine Diabetes Society. Bariatric surgery update in a patient with diabetes and kidney disease. Part 2

La prevalencia de obesidad y diabetes mellitus se asocia al desarrollo de enfermedad renal crónica y estadios terminales de la misma. En individuos con obesidad se produce un mecanismo de hiperfiltración, probablemente compensatorio para satisfacer la alta demanda metabólica asociada al aumento del peso corporal, con la presencia de proteinuria en individuos sin enfermedad renal. La histopatología muestra una glomeruloesclerosis focal y segmentaria relacionada con la obesidad en un marco de glomerulomegalia. La cirugía metabólica es el medio más efectivo para obtener una pérdida de peso sustancial y persistente. Se ha demostrado la superioridad de la cirugía sobre el tratamiento médico no solo para lograr un mejor control glucémico, sino también para la reducción de los factores de riesgo cardiovascular. Los mecanismos parecen extenderse más allá de la magnitud de la pérdida de peso e incluyen mejoras tanto en los perfiles de incretinas como en la secreción y la sensibilidad a la insulina. El Comité de Nefropatía de la Sociedad Argentina de Diabetes realizó esta revisión sobre los mecanismos involucrados en la obesidad como causa de enfermedad renal o empeoramiento de la misma por diabetes, y los mecanismos a través de los cuales la cirugía bariátrica beneficiaría a los pacientes con diabetes y enfermedad renal crónica en todos los estadios de la misma, así como los controles pre y posquirúrgicos en este tipo de cirugías.

The prevalence of obesity and diabetes mellitus are associated with the development of chronic kidney disease and its terminal stages. In individuals affected by obesity, a probably compensatory hyperfiltration mechanism occurs to satisfy the high metabolic demand associated with increased body weight; it is also associated with the presence and development of proteinuria in individuals without kidney disease. Histopathology shows obesity-related focal and segmental glomerulosclerosis in a setting of glomerulomegaly. Metabolic surgery is the most effective means of obtaining substantial and lasting weight loss. The superiority of surgery over medical treatment has been demonstrated only to achieve better glycemic control, as well as a reduction in cardiovascular risk factors. The mechanisms appear to extend beyond the magnitude of weight loss and include improvements in incretin profiles, insulin secretion, and insulin sensitivity. The Nephropathy Committee of the Argentine Diabetes Society carried out this review on mechanisms involved in obesity as a cause of kidney disease or worsening of kidney disease due to diabetes, the mechanisms by which bariatric surgery would benefit patients with diabetes and kidney disease chronic and its terminal stages, the pre and post-surgical controls that should be performed by patients undergoing this type of surgery

Jornadas del Comité de Nefropatía de la Sociedad Argentina de Diabetes. Actualización de cirugía bariátrica en paciente con diabetes y enfermedad renal. Parte 1 / Conference of the Nephropathy Committee of the Argentine Society of Diabetes. Bariatric surgery update in a patient with diabetes and kidney disease. Part 1

La prevalencia de obesidad y diabetes mellitus se asocia al desarrollo de enfermedad renal crónica y estadios terminales de la misma. En individuos con obesidad, se produce un mecanismo de hiperfiltración, probablemente compensatorio para satisfacer la alta demanda metabólica asociada al aumento del peso corporal, con la presencia de proteinuria, en individuos sin enfermedad renal. La histopatología muestra una glomeruloesclerosis focal y segmentaria relacionada con la obesidad en un marco de glomerulomegalia. La cirugía metabólica es el medio más efectivo para obtener una pérdida de peso sustancial y persistente. Se ha demostrado la superioridad de la cirugía sobre el tratamiento médico no solo para lograr un mejor control glucémico, sino también para la reducción de los factores de riesgo cardiovascular. Los mecanismos parecen extenderse más allá de la magnitud de la pérdida de peso e incluyen mejoras tanto en los perfiles de incretinas como en la secreción y la sensibilidad a la insulina. El Comité de Nefropatía de la Sociedad Argentina de Diabetes realizó esta revisión sobre los mecanismos involucrados en la obesidad como causa de enfermedad renal o empeoramiento de la misma por diabetes, y los mecanismos a través de los cuales la cirugía bariátrica beneficiaría a los pacientes con diabetes y enfermedad renal crónica en todos los estadios de la misma, así como los controles pre y posquirúrgicos en este tipo de cirugías.

The prevalence of obesity and diabetes mellitus are associated with the development of chronic kidney disease and its terminal stages. In individuals affected by obesity, a probably compensatory hyperfiltration mechanism occurs to satisfy the high metabolic demand associated with increased body weight; it is also associated with the presence and development of proteinuria in individuals without kidney disease. Histopathology shows obesity-related focal and segmental glomerulosclerosis in a setting of glomerulomegaly. Metabolic surgery is the most effective means of obtaining substantial and lasting weight loss. The superiority of surgery over medical treatment has been demonstrated only to achieve better glycemic control, as well as a reduction in cardiovascular risk factors. The mechanisms appear to extend beyond the magnitude of weight loss and include improvements in incretin profiles, insulin secretion, and insulin sensitivity. The Nephropathy Committee of the Argentine Diabetes Society carried out this review on mechanisms involved in obesity as a cause of kidney disease or worsening of kidney disease due to diabetes, the mechanisms by which bariatric surgery would benefit patients with diabetes and kidney disease chronic and its terminal stages, the pre and post-surgical controls that should be performed by patients undergoing this type of surgery.

C3 Glomerulopathy, a pathology with scarce evidence. A case report.

C3 Glomerulonephritis (C3GN) is a rare disease with an estimated incidence of 1-2 cases per million, caused by an alteration in the alternative complement pathway, although its complete physiopathology remains uncertain. Treatment evidence is poor. Immunosuppressive therapy can be initiated in more severe cases. Progression rates to end stage kidney disease are of up to 50% within a decade, and the posttransplant recurrence rates of 45-60%. We describe the case of a young man without any past medical history, with lower extremities edema, dyspnea, and kidney function deterioration. The patient was ultimately diagnosed with C3GN.

Comparison of urinary protein-to-creatinine ration, serum albumin, serum creatinine and systolic arterial blood pressure of glomerular injury cases in dogs with chronic kidney disease / Comparação da razão proteína creatinina urinárias, albumina sérica, creatinina sérica e pressão arterial sistólica das lesões glomerulares encontradas em cães com doença renal crônica

This study aims at assessing the prevalence of glomerular alterations in dogs with chronic kidney disease (CKD) and comparing the clinical and laboratory parameters. The tests conducted include a double-blind histopathological assay conducted by two pathologists, urine tests including inactive sediment, urinary protein-to-creatinine (UPC), serum albumin and serum creatinine, as well as measurement of the systolic arterial blood pressure. The prevalence of glomerular injuries was determined and the predominant injury was compared with a group comprised of the remaining injuries. The study included 24 dogs with CKD. The results revealed a predominance of membranous glomerular alterations 17/24 (70,83%), followed by glomerulosclerosis 3/24 (12,50%), membranoproliferative injuries 2/24, glomerulocystic atrophy 1/24 and glomerular amyloidosis 1/24. Amyloidosis presented the highest UPC while the membranoproliferative injury presented the lowest mean concentration of serum albumin. Higher values in the UPC did not correspond with lower mean serum albumin values. Glomerulosclerosis presented the highest mean systolic blood pressure and glomerular atrophy presented the highest creatinine values. When comparing membranous injuries with a group comprised of the remaining injuries, the UPC did not present significant differences between the groups. Renal amyloidosis was included in the group with the lowest systolic arterial blood pressure values while membranoproliferative injury was included in the group with highest UPC. The group called "others" presented the highest creatinine value. Dogs with CKD may present several types of glomerular injuries with similar clinical and laboratory profiles. This study observed a predominance of membranous glomerular injuries, followed by membranoproliferative injuries, glomerulocystic atrophy and amyloidosis.(AU)

O estudo teve como objetivo avaliar a prevalência das alterações glomerulares dos cães doentes renais crônicos e comparar parâmetros clínicos e laboratoriais. Foi realizada análise histopatológica por dois patologistas pelo método duplo-cego, análise dos exames de urina com sedimento inativo, razão proteína creatinina urinárias, avaliação da creatinina e albumina séricas e pressão arterial sistólica. Determinouse a prevalência das lesões glomerulares e foi comparado o grupo de lesões predominante com um grupo abrangendo as demais lesões. Foram incluídos neste estudo 24 cães doentes renais crônicos. Após análise foi observado predomínio de alterações glomerulares membranosas (n=17), seguidos de glomeruloesclerose (n=3), lesões membranoproliferativas (n=2), atrofia glomerulocística (n=1) e amiloidose glomerular (n=1). A amiloidose apresentou maior razão proteína creatinina urinárias e a lesão membranoproliferativa obteve a menor média de albumina sérica. Maiores valores da razão proteína creatinina urinárias não corresponderam com menor média de albumina sérica. Glomeruloesclerose teve maior média de pressão arterial sistólica. O maior valor de creatinina foi observado no caso de atrofia glomerular. Quando comparados lesões membranosas com um grupo dos demais tipos de lesões, RPC não diferiu entre os grupos. Amiloidose renal estava inclusa no grupo de animais com valores mais baixos de pressão arterial sistólica e a lesão membranoproliferativa estava entre os animais com maior RPC. O grupo denominado "outros" teve maior valor de creatinina. Cães com doença renal crônica podem apresentar diferentes tipos de lesões glomerulares com quadros clínicos e laboratoriais semelhantes. Há um predomínio de lesões glomerulares membranosas, seguidas pela glomeruloesclerose, lesão membranoproliferativa, atrofia glomerulocística e amiloidose.(AU)

Brazilian Consortium for the Study on Renal Diseases Associated With COVID-19: A Multicentric Effort to Understand SARS-CoV-2-Related Nephropathy.

Kidney involvement appears to be frequent in coronavirus disease 2019 (COVID-19). Despite this, information concerning renal involvement in COVID-19 is still scarce. Several mechanisms appear to be involved in the complex relationship between the virus and the kidney. Also, different morphological patterns have been described in the kidneys of patients with COVID-19. For some authors, however, this association may be just a coincidence. To investigate this issue, we propose assessing renal morphology associated with COVID-19 at the renal pathology reference center of federal university hospitals in Brazil. Data will come from a consortium involving 17 federal university hospitals belonging to Empresa Brasileira de Serviços Hospitalares (EBSERH) network, as well as some state hospitals and an autopsy center. All biopsies will be sent to the referral center for renal pathology of the EBSERH network. The data will include patients who had coronavirus disease, both alive and deceased, with or without pre-existing kidney disease. Kidney biopsies will be analyzed by light, fluorescence, and electron microscopy. Furthermore, immunohistochemical (IHC) staining for various inflammatory cells (i.e., cells expressing CD3, CD20, CD4, CD8, CD138, CD68, and CD57) as well as angiotensin-converting enzyme 2 (ACE2) will be performed on paraffinized tissue sections. In addition to ultrastructural assays, in situ hybridization (ISH), IHC and reverse transcription-polymerase chain reaction (RT-PCR) will be used to detect Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) in renal tissue. For the patients diagnosed with Collapsing Glomerulopathy, peripheral blood will be collected for apolipoprotein L-1 (APOL1) genotyping. For patients with thrombotic microangiopathy, thrombospondin type 1 motif, member 13 (ADAMTS13), antiphospholipid, and complement panel will be performed. The setting of this study is Brazil, which is second behind the United States in highest confirmed cases and deaths. With this complete approach, we hope to help define the spectrum and impact, whether immediate or long-term, of kidney injury caused by SARS-CoV-2.

Alteration of the Fatty Acid Metabolism in the Rat Kidney Caused by the Injection of Serum from Patients with Collapsing Glomerulopathy.

Patients with collapsing glomerulopathy (CG) have marked proteinuria that rapidly progresses to chronic renal failure. In this study, we investigated if the nephropathy produced in a rat model by the injection of serum from CG patients induced alterations in fatty acid (FA) metabolism. Twenty-four female Sprague-Dawley rats were divided into four groups of six rats each: Group I, control rats (C); Group II, rats that received injections of 1 mL of 0.9% NaCl saline solution (SS); Group III, rats injected with 25 mg/mL of serum from healthy subjects (HS); and Group IV, rats injected with 25 mg/mL of serum from CG patients. In all groups, the systolic blood pressure (SBP), proteinuria, creatinine clearance (CC), cholesterol and total FA composition in the kidney and serum were evaluated. The administration of serum from CG patients to rats induced glomerular collapse, proteinuria, reduced CC and elevated SBP (p ≤ 0.01) in comparison with the C, SS and HS rats. The FA composition of the serum of rats that received the CG serum showed an increase in palmitic acid (PA) and a decrease in arachidonic acid (AA) when compared to serum from HS (p ≤ 0.02). In rats receiving the CG serum, there was also a decrease in the AA in the kidney but there was an increase in the PA in the serum and kidney (p ≤ 0.01). These results suggest that the administration of serum from CG patients to rats induces alterations in FA metabolism including changes in PA and in AA, which are precursors for the biosynthesis of the prostaglandins that are involved in the elevation of SBP and in renal injury. These changes may contribute to collapsing glomerulopathy disease.

Lack of adiponectin in mice accelerates high-fat diet-induced progression of chronic kidney disease.

Obesity is an independent risk factor for the development of chronic kidney disease. The pathophysiology of the obesity-induced kidney injury is complex, but evidence suggests the involvement of reduced adiponectin levels and signaling. We investigated the extent by which adiponectin contributes to the establishment and progression of renal disease in wild type (WT) and adiponectin null (adipoKO) mice fed a control or a high-fat diet (HFD) for 16 weeks. HFD induced obesity, kidney hypertrophy, albuminuria, renal lipid accumulation and decreased nephrin expression in both mice genotypes. Notably, HFD in adipoKO mice exacerbated progression of albuminuria in comparison to WT mice. In addition, lack of adiponectin per se increased kidney weight, reduced nephrin levels, up-regulated Fabp4 expression, reduced Cpt1a expression and increased miR-130 levels in kidney. Our results demonstrate that lack of adiponectin combined with a HFD contributes to accelerated kidney dysfunction.

Renal protective effect of pinitol in experimental diabetes.

Pinitol is a natural antidiabetic agent shown to prevent or ameliorate metabolic and overall vascular and neural function. In the present study we have evaluated the potential benefits of pinitol on renal function of streptozotocin (STZ)-induced diabetic rats. Both euglycemic or 8-week or 16-week diabetic rats were treated with either saline (1 ml/kg/12h; p.o) or pinitol (20 mg/kg/12h; p.o). The renal function was evaluated by using metabolic cages, renal hemodynamic and tubular parameters measurements. Histological examination and evaluation of the protein expression of renal markers such as nephrin, TGFß and pERK were also performed. Pinitol decreased by 50% the increased urinary albumin/creatinine ratio in both 8-week and 16 week diabetic rats. In addition, the glomerular volume of 16-week rats increased by 55% and this increase was blunted by pinitol. Remarkably, pressure-natriuresis was completely blunted in both 8 and 16-week diabetic rats but this impairment was prevented by pinitol in both treatment regimens. Pinitol ameliorated renal lesions and also prevented the decrease in nephrin expression and the increase of pERK and TGFß expression in both diabetic groups. Natriuresis due to high renal perfusion pressure increased 7-fold in control animals but was blocked in 16-week diabetic rats and remarkably pinitol partially restored pressure natriuresis (3-fold increase in sodium excretion during pressure natriuresis). Pinitol prevents and ameliorates albuminuria, glomerular expansion, impairment of pressure-natriuresis, renal structural alterations and changes of renal markers and has the potential to be tested for the prevention of diabetic kidney disease.

Mechanisms of Podocyte Detachment, Podocyturia, and Risk of Progression of Glomerulopathies.

BACKGROUND: Glomerulopathies are the main cause of ESRD. Primary or secondary causes of glomerular diseases comprise more than 70% of cases that end up in renal replacement therapies. SUMMARY: The total glomerular mass that each individual contains is key to maintaining normal kidney function. Diabetes, hypertension, and any primary or secondary glomerulopathy may threaten the normal glomerular function. In fact, any glomerular insult may alter the glomerular filtration barrier, which in turn is composed by the podocyte, the glomerular basement membrane, and the capillary endothelial cell. Deposition of immune complexes, antibodies, or complement components at the subepithelial, intramembranous, or subendothelial space, and mutations in podocyte, slit diaphragm, or glomerular basement membrane proteins or enzymes are the main etiologies of glomerular alterations. Podocytes are glomerular cells that do not divide under normal circumstances. In this respect, maintenance of the absolute podocyte number per glomer-ulus is critical for normal glomerular function. As the insult progresses, podocytes start to detach from the glomerular basement membrane. When the podocyte loss is over 40% in a glomerulus, glomerulosclerosis develops, and obliteration of the glomerulus is the rule. In clinical grounds, this phenomenon is diagnosed mainly by proteinuria and a decline in glomerular filtration rate. KEY MESSAGES: In this review article, the impact of podocyturia in glomerular diseases and the main mechanisms of podocyte detachment are discussed. Finally, potential targets of therapeutic approach are suggested.

Primary Membranous Nephropathy With Extremely High Levels Of Ca-125 / Nefropatía Membranosa Primaria Con Niveles Extremadamente Altos De Ca-125

Abstract Membranous nephropathy is a glomerular disease that causes nephrotic syndrome. Absent phospholipase A2 receptor antibodies and absent staining with IgG4 may be linked to malignancy-associated MN. Here we present a case that defies that suggestion. A 42-year-old female presented with anasarca. Kidney biopsy revealed membranous nephropathy, stained positive for IgG but negative for IgG4. Absent phospholipase A2 receptor antibodies was negative. Abdominal tomography revealed a partial thrombosis of the left ovarian vein which raised suspicion for ovarian cancer. Even though her ovaries did not uptake FDG on PET scan, a carbohydrate antigen-125 was ordered. She had extremely high levels of carbohydrate antigen-125 which was unexpected in the course of benign events. Thorax CT, endoscopy, colonoscopy, mammography, and positron emission tomography were clear in terms of malignancy. Samples from both pleural effusion and ascites were consistent with transudate. Tuberculosis tests were negative. Cytology samples were negative for malign cells. Exploratory surgery was planned but rejected by the patient. She was treated as primary disease with cyclosporine and methylprednisolone. Rituximab was off-limits due to insurance rules. She had prompt and excellent response. Steroids were tapered and stopped at sixth month and cyclosporine at twelfth month. In her 36 months of drug-free follow up there has been no disease recurrence or a sign of cancer. Even when all odds are towards malignancy-associated membranous nephropathy, primary disease is still a possibility. We need better markers for malignancy-associated membranous nephropathy.A very high level of CA-125 does not necessarily mean cancer.

Resumen La nefropatía membranosa es una enfermedad glomerular que causa el síndrome nefrótico. La ausencia de anticuerpos contra el receptor de fosfolipasa A2 y de tinción para IgG4 puede deberse a una nefropatía membranosa asociada a cáncer. A continuación, se presenta un caso que desafía esta sugerencia. Una paciente de 42 años realizó una consulta por anasarca. A partir de la biopsia de riñón, se diagnosticó nefropatía membranosa con tinción positiva para IgG, pero negativa para IgG4. No se detectó la presencia de anticuerpos contra el receptor de fosfolipasa A2. La tomografía abdominal reveló una trombosis parcial en la vena ovárica izquierda, lo cual generó sospecha de cáncer de ovario. Si bien los ovarios no mostraron absorción de FDG en la tomografía por emisión de positrones, se solicitó una prueba de antígeno carbohidrato 125. Se le detectaron niveles elevados del antígeno carbohidrato 125, lo cual no es esperable en casos de eventos benignos. La tomografía computarizada de tórax, endoscopía, colonoscopía, mamografía y tomografía por emisión de positrones no mostraron tumores. Las muestras de derrame pleural y de ascitis fueron indicativas de trasudado. Las pruebas de tuberculosisarrojaron resultados negativos. El examen citológico fue negativo para células malignas. Se sugirió una cirugía exploradora, pero la paciente no aceptó. Se la trató con ciclosporina y metilprednisolona por enfermedad primaria. No se utilizó rituximab por reglas de su cobertura médica. La paciente tuvo una excelente respuesta al tratamiento de forma rápida. Los esteroides se disminuyeron de forma progresiva y se suspendieron a los seis meses, y la ciclosporina, a los doce meses. Durante los 36 meses de seguimiento sin medicación no ha habido recidiva ni signos de cáncer. Incluso cuando existen grandes probabilidades de que se trate de una nefropatía membranosa asociada a cáncer, aún es posible que se trate de una enfermedad primaria. Es necesario contar con mejores marcadores de nefropatía membranosa asociada a cáncer. Un nivel elevado de CA-125 no necesariamente es indicador de cáncer.

A novel single amino acid deletion impairs fibronectin function and causes familial glomerulopathy with fibronectin deposits: case report of a family.

BACKGROUND: Glomerulopathy with fibronectin deposits is an autosomal dominant disease associated with proteinuria, hematuria, hypertension and renal function decline. Forty percent of the cases are caused by mutations in FN1, the gene that encodes fibronectin. CASE PRESENTATION: This report describes two cases of Glomerulopathy with fibronectin deposits, involving a 47-year-old father and a 14-year-old son. The renal biopsies showed glomeruli with endocapillary hypercellularity and large amounts of mesangial and subendothelial eosinophilic deposits. Immunohistochemistry for fibronectin was markedly positive. Whole exome sequencing identified a novel FN1 mutation that leads to an amino-acid deletion in both patients (Ile1988del), a variant that required primary amino-acid sequence analysis for assessment of pathogenicity. Our primary sequence analyses revealed that Ile1988 is very highly conserved among relative sequences and is positioned in a C-terminal FN3 domain containing heparin- and fibulin-1-binding sites. This mutation was predicted as deleterious and molecular mechanics simulations support that it can change the tertiary structure and affect the complex folding and its molecular functionality. CONCLUSION: The current report not only documents the occurrence of two GFND cases in an affected family and deeply characterizes its anatomopathological features but also identifies a novel pathogenic mutation in FN1, analyzes its structural and functional implications, and supports its pathogenicity.

Gut microbial metabolite butyrate protects against proteinuric kidney disease through epigenetic- and GPR109a-mediated mechanisms.

Butyrate is a short-chain fatty acid derived from the metabolism of indigestible carbohydrates by the gut microbiota. Butyrate contributes to gut homeostasis, but it may also control inflammatory responses and host physiology in other tissues. Butyrate inhibits histone deacetylases, thereby affecting gene transcription, and also signals through the metabolite-sensing G protein receptor (GPR)109a. We produced an mAb to mouse GPR109a and found high expression on podocytes in the kidney. Wild-type and Gpr109a-/- mice were induced to develop nephropathy by a single injection of Adriamycin and treated with sodium butyrate or high butyrate-releasing high-amylose maize starch diet. Butyrate improved proteinuria by preserving podocyte at glomerular basement membrane and attenuated glomerulosclerosis and tissue inflammation. This protective phenotype was associated with increased podocyte-related proteins and a normalized pattern of acetylation and methylation at promoter sites of genes essential for podocyte function. We found that GPR109a is expressed by podocytes, and the use of Gpr109a-/- mice showed that the protective effects of butyrate depended on GPR109a expression. A prebiotic diet that releases high amounts of butyrate also proved highly effective for protection against kidney disease. Butyrate and GPR109a play a role in the pathogenesis of kidney disease and provide one of the important molecular connections between diet, the gut microbiota, and kidney disease.-Felizardo, R. J. F., de Almeida, D. C., Pereira, R. L., Watanabe, I. K. M., Doimo, N. T. S., Ribeiro, W. R., Cenedeze, M. A., Hiyane, M. I., Amano, M. T., Braga, T. T., Ferreira, C. M., Parmigiani, R. B., Andrade-Oliveira, V., Volpini, R. A., Vinolo, M. A. R., Mariño, E., Robert, R., Mackay, C. R., Camara, N. O. S. Gut microbial metabolite butyrate protects against proteinuric kidney disease through epigenetic- and GPR109a-mediated mechanisms.