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1.
BMC Nephrol ; 20(1): 340, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477057

RESUMO

BACKGROUND: Kidney transplantation is the treatment of choice in end-stage renal disease due to Alport syndrome (AS). However, the chances of finding an adequate living-related donor in AS are much worse compared to non-heritable conditions. Successful cases of related living-donor transplantation mostly refer to X-linked AS but are rarely reported in genetically confirmed autosomal AS. CASE PRESENTATION: We describe the outcome of an exceptional AB0-incompatible kidney donation from father to son in a family with altered COL4A3. While decision-making was based on extensive clinical donor evaluation prior to transplantation, we analyzed the underlying genetic background in retrospect and associated these findings with the phenotype in all available family members. While biallelic COL4A3 variants caused autosomal recessive AS (ARAS) in the son (recipient), heterozygous family members, including the father (donor), showed minimal renal involvement and high-frequency sensorineural hearing impairment later in life indicating mild autosomal dominant Alport syndrome (ADAS). The recipient's successful participation in the European and World Transplant Games is a testament to the positive outcome of transplantation. CONCLUSIONS: In summary, living-related donor transplantation may be successful in autosomal AS, provided that thorough clinical and genetic evaluation of potential donors is performed. However, unrelated kidney transplantation should be given priority upon unpredictable genetic risk. Individual genetic variant interpretation is an important component of personalized donor assessment and will help to better predict genetic risk in the future.


Assuntos
Autoantígenos/genética , Colágeno Tipo IV/genética , Testes Genéticos/métodos , Transplante de Rim/métodos , Doadores Vivos , Nefrite Hereditária/genética , Nefrite Hereditária/cirurgia , Adulto , Humanos , Masculino , Nefrite Hereditária/diagnóstico , Linhagem , Estudos Retrospectivos
2.
J Am Soc Nephrol ; 28(11): 3262-3277, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28814510

RESUMO

Thrombospondin type 1 domain-containing 7A (THSD7A) is a target for autoimmunity in patients with membranous nephropathy (MN). Circulating autoantibodies from patients with THSD7A-associated MN have been demonstrated to cause MN in mice. However, THSD7A-associated MN is a rare disease, preventing the use of patient antibodies for larger experimental procedures. Therefore, we generated antibodies against the human and mouse orthologs of THSD7A in rabbits by coimmunization with the respective cDNAs. Injection of these anti-THSD7A antibodies into mice induced a severe nephrotic syndrome with proteinuria, weight gain, and hyperlipidemia. Immunofluorescence analyses revealed granular antigen-antibody complexes in a subepithelial location along the glomerular filtration barrier 14 days after antibody injection, and immunohistochemistry for rabbit IgG and THSD7A as well as ultrastructural analyses showed the typical characteristics of human MN. Mice injected with purified IgG from rabbit serum that was taken before immunization failed to develop any of these changes. Notably, MN developed in the absence of detectable complement activation, and disease was strain dependent. In vitro, anti-THSD7A antibodies caused cytoskeletal rearrangement and activation of focal adhesion signaling. Knockdown of the THSD7A ortholog, thsd7aa, in zebrafish larvae resulted in altered podocyte differentiation and impaired glomerular filtration barrier function, with development of pericardial edema, suggesting an important role of THSD7A in glomerular filtration barrier integrity. In summary, our study introduces a heterologous mouse model that allows further investigation of the molecular events that underlie MN.


Assuntos
Anticorpos/fisiologia , Antígenos de Superfície/imunologia , Glomerulonefrite Membranosa/imunologia , Proteínas de Membrana/imunologia , Trombospondinas/imunologia , Animais , Antígenos de Superfície/fisiologia , Modelos Animais de Doenças , Humanos , Masculino , Proteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Coelhos , Ratos , Ratos Sprague-Dawley , Trombospondinas/fisiologia
3.
J Am Soc Nephrol ; 28(2): 520-531, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27436855

RESUMO

Thrombospondin type 1 domain-containing 7A (THSD7A) is a target antigen identified in adult membranous nephropathy (MN) along with the major antigen phospholipase A2 receptor 1 (PLA2R1). The prevalence of THSD7A-Ab-positive patients is unknown, and it is unclear whether the clinical presentation differs between patients positive for PLA2R1-Ab or THSD7A-Ab. We screened serum samples of 1276 patients with MN from three different cohorts for the presence of THSD7A-Ab by Western blot analysis and a newly developed indirect immunofluorescence test (IFT). Compared with Western blot analysis, the IFT had a 92% sensitivity and a 100% specificity. The prevalence of THSD7A-associated MN in a prospective cohort of 345 patients with MN was 2.6%, and most were women. In this cohort, the percentage of patients with THSD7A-associated MN and malignant disease significantly exceeded that of patients with PLA2R1-associated MN and malignant disease. In all cohorts, we identified 40 patients with THSD7A-associated MN, eight of whom developed a malignancy within a median time of 3 months from diagnosis of MN. In one patient with THSD7A-associated MN and metastases of an endometrial carcinoma, immunohistochemistry showed THSD7A expression on the metastatic cells and within follicular dendritic cells of the metastasis-infiltrated lymph node. We conclude that the IFT allows sensitive and specific measurement of circulating THSD7A-Ab in patients with MN. Patients with THSD7A-associated MN differ in their clinical characteristics from patients with PLA2R1-associated MN, and more intensive screening for the presence of malignancies may be warranted in those with THSD7A-associated MN.


Assuntos
Autoanticorpos/sangue , Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/imunologia , Trombospondinas/imunologia , Adulto , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos
4.
N Engl J Med ; 371(24): 2277-2287, 2014 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-25394321

RESUMO

BACKGROUND: Idiopathic membranous nephropathy is an autoimmune disease. In approximately 70% of patients, it is associated with autoantibodies against the phospholipase A2 receptor 1 (PLA2R1). Antigenic targets in the remaining patients are unknown. METHODS: Using Western blotting, we screened serum samples from patients with idiopathic membranous nephropathy, patients with other glomerular diseases, and healthy controls for antibodies against human native glomerular proteins. We partially purified a putative new antigen, identified this protein by means of mass spectrometry of digested peptides, and validated the results by analysis of recombinant protein expression, immunoprecipitation, and immunohistochemical analysis. RESULTS: Serum samples from 6 of 44 patients in a European cohort and 9 of 110 patients in a Boston cohort with anti-PLA2R1-negative idiopathic membranous nephropathy recognized a glomerular protein that was 250 kD in size. None of the serum samples from the 74 patients with idiopathic membranous nephropathy who were seropositive for anti-PLA2R1 antibodies, from the 76 patients with other glomerular diseases, and from the 44 healthy controls reacted against this antigen. Although this newly identified antigen is clearly different from PLA2R1, it shares some biochemical features, such as N-glycosylation, membranous location, and reactivity with serum only under nonreducing conditions. Mass spectrometry identified this antigen as thrombospondin type-1 domain-containing 7A (THSD7A). All reactive serum samples recognized recombinant THSD7A and immunoprecipitated THSD7A from glomerular lysates. Moreover, immunohistochemical analyses of biopsy samples from patients revealed localization of THSD7A to podocytes, and IgG eluted from one of these samples was specific for THSD7A. CONCLUSIONS: In our cohort, 15 of 154 patients with idiopathic membranous nephropathy had circulating autoantibodies to THSD7A but not to PLA2R1, a finding that suggests a distinct subgroup of patients with this condition. (Funded by the French National Center for Scientific Research and others.).


Assuntos
Autoanticorpos/sangue , Glomerulonefrite Membranosa/imunologia , Receptores da Fosfolipase A2/imunologia , Trombospondinas/imunologia , Western Blotting , Estudos de Casos e Controles , Glomerulonefrite Membranosa/sangue , Humanos , Glomérulos Renais/metabolismo , Receptores da Fosfolipase A2/sangue , Receptores da Fosfolipase A2/metabolismo , Trombospondinas/sangue , Trombospondinas/metabolismo
5.
J Am Soc Nephrol ; 26(9): 2105-17, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25762060

RESUMO

ANCA-associated vasculitis is the most frequent cause of crescentic GN. To define new molecular and/or cellular biomarkers of this disease in the kidney, we performed microarray analyses of renal biopsy samples from patients with ANCA-associated crescentic GN. Expression profiles were correlated with clinical data in a prospective study of patients with renal ANCA disease. CC chemokine ligand 18 (CCL18), acting through CC chemokine receptor 8 (CCR8) on mononuclear cells, was identified as the most upregulated chemotactic cytokine in patients with newly diagnosed ANCA-associated crescentic GN. Macrophages and myeloid dendritic cells in the kidney were detected as CCL18-producing cells. The density of CCL18(+) cells correlated with crescent formation, interstitial inflammation, and impairment of renal function. CCL18 protein levels were higher in sera of patients with renal ANCA disease compared with those in sera of patients with other forms of crescentic GN. CCL18 serum levels were higher in patients who suffered from ANCA-associated renal relapses compared with those in patients who remained in remission. Using a murine model of crescentic GN, we explored the effects of the CCL18 murine functional analog CCL8 and its receptor CCR8 on kidney function and morphology. Compared with wild-type mice, Ccr8(-/-) mice had significantly less infiltration of pathogenic mononuclear phagocytes. Furthermore, Ccr8(-/-) mice maintained renal function better and had reduced renal tissue injury. In summary, our data indicate that CCL18 drives renal inflammation through CCR8-expressing cells and could serve as a biomarker for disease activity and renal relapse in ANCA-associated crescentic GN.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Quimiocinas CC/sangue , Glomerulonefrite/etiologia , Glomerulonefrite/metabolismo , Idoso , Animais , Biomarcadores/sangue , Quimiocina CCL8/genética , Quimiocina CCL8/metabolismo , Quimiocinas CC/análise , Células Dendríticas/química , Feminino , Glomerulonefrite/patologia , Glomerulonefrite/fisiopatologia , Humanos , Macrófagos/química , Masculino , Camundongos , Pessoa de Meia-Idade , Estudos Prospectivos , Análise Serial de Proteínas , Receptores CCR8/genética , Receptores CCR8/metabolismo , Regulação para Cima
6.
J Am Soc Nephrol ; 26(1): 55-66, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24904089

RESUMO

Neutrophil trafficking to sites of inflammation is essential for the defense against bacterial and fungal infections, but also contributes to tissue damage in TH17-mediated autoimmunity. This process is regulated by chemokines, which often show an overlapping expression pattern and function in pathogen- and autoimmune-induced inflammatory reactions. Using a murine model of crescentic GN, we show that the pathogenic TH17/IL-17 immune response induces chemokine (C-X-C motif) ligand 5 (CXCL5) expression in kidney tubular cells, which recruits destructive neutrophils that contribute to renal tissue injury. By contrast, CXCL5 was dispensable for neutrophil recruitment and effective bacterial clearance in a murine model of acute bacterial pyelonephritis. In line with these findings, CXCL5 expression was highly upregulated in the kidneys of patients with ANCA-associated crescentic GN as opposed to patients with acute bacterial pyelonephritis. Our data therefore identify CXCL5 as a potential therapeutic target for the restriction of pathogenic neutrophil infiltration in TH17-mediated autoimmune diseases while leaving intact the neutrophil function in protective immunity against invading pathogens.


Assuntos
Quimiocina CXCL5/metabolismo , Glomerulonefrite/patologia , Neutrófilos/metabolismo , Células Th17/citologia , Animais , Quimiocina CXCL1/metabolismo , Quimiocinas/metabolismo , Modelos Animais de Doenças , Células Epiteliais/citologia , Feminino , Glomerulonefrite/metabolismo , Glomerulonefrite/microbiologia , Inflamação , Interleucina-17/metabolismo , Rim/metabolismo , Túbulos Renais/metabolismo , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Infiltração de Neutrófilos/imunologia , Regulação para Cima
7.
Kidney Int ; 88(1): 160-6, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25671765

RESUMO

Hyperuricemia is very common in industrialized countries and known to promote vascular smooth muscle cell proliferation. Juvenile hyperuricemia is a hallmark of uromodulin-associated kidney disease characterized by progressive interstitial renal fibrosis leading to end-stage renal disease within decades. Here we describe a member of a Polish-German family with a history of familial background of chronic kidney disease, hyperuricemia, and gout. This patient had hypertension because of bilateral small renal arteries, hyperuricemia, and chronic kidney disease. Clinical and molecular studies were subsequently performed in 39 family members, which included a physical examination, Duplex ultrasound of the kidneys, laboratory tests for renal function, and urine analysis. In eight family members contrast-enhanced renal artery imaging by computed tomography-angiography or magnetic resonance imaging was conducted and showed that bilateral non-arteriosclerotic small caliber renal arteries were associated with hyperuricemia and chronic kidney disease. Of the 26 family members who underwent genotyping, 11 possessed the P236R mutation (c.707C>G) of the uromodulin gene. All family members with a small caliber renal artery carried the uromodulin P236R mutation. Statistical analysis showed a strong correlation between reduced renal artery lumen and decreased estimated glomerular filtration rate. Thus, bilateral small caliber renal arteries are a new clinical phenotype associated with an uromodulin mutation.


Assuntos
Taxa de Filtração Glomerular , Gota/genética , Hiperuricemia/genética , Nefropatias/genética , Artéria Renal/diagnóstico por imagem , Artéria Renal/patologia , Uromodulina/genética , Adolescente , Adulto , Idoso , Angiografia , Criança , Doença Crônica , Feminino , Genótipo , Gota/complicações , Gota/fisiopatologia , Humanos , Hiperuricemia/complicações , Hiperuricemia/fisiopatologia , Nefropatias/complicações , Nefropatias/fisiopatologia , Falência Renal Crônica/etiologia , Túbulos Renais Distais/química , Masculino , Pessoa de Meia-Idade , Mutação , Tamanho do Órgão , Linhagem , Fenótipo , Ácido Úrico/sangue , Uromodulina/análise , Adulto Jovem
8.
Nephrol Dial Transplant ; 30(11): 1862-9, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26142398

RESUMO

BACKGROUND: Phospholipase A2 receptor antibodies (PLA2R-Ab) and thrombospondin type-1 domain-containing 7A antibodies (THSD7A-Ab) are present in 70-80% of patients with membranous nephropathy (MN). Little, however, is known about the pathogenesis of MN and the clinical outcome in PLA2R-Ab- and THSD7A-Ab-negative patients. METHODS: In this prospective multicentre observational study, the clinical outcome of 37 patients with biopsy-proven MN who were negative for PLA2R-Ab and THSD7A-Ab in the serum was analysed. RESULTS: A total of 198 patients were screened for inclusion in the study. Of these, 157 patients were positive for PLA2R-Ab and 4 patients for THSD7A-Ab. The remaining 37 patients were negative for both antibodies were and included in this study. Six patients died during the follow-up, five because of malignant diseases and one of an infection. One patient went into end-stage renal disease, and two patients were lost to follow-up. The remaining 28 patients were followed for at least 24 months (35.6 ± 8.9 months). Seventeen patients received immunosuppressive (IS) therapy, and 11 received supportive care only. At the end of the follow-up, 14 of the 17 patients treated with immunosuppressants and 10 of 11 patients on supportive therapy had a remission of proteinuria. The time to reach remission of proteinuria and serum creatinine levels at the end of the follow-up were not different between both groups. A univariate Cox regression analysis indicated that the use of immunosuppression did not alter the chance to reach a remission of proteinuria. CONCLUSIONS: A high number of PLA2R-Ab- and THSD7A-Ab-negative patients with MN have a good prognosis and might not need IS therapy.


Assuntos
Autoanticorpos/sangue , Glomerulonefrite Membranosa/fisiopatologia , Proteinúria/fisiopatologia , Receptores da Fosfolipase A2/imunologia , Trombospondinas/imunologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Proteinúria/etiologia , Remissão Espontânea , Resultado do Tratamento , Adulto Jovem
9.
Pediatr Nephrol ; 30(9): 1477-83, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25903641

RESUMO

BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS) is still regarded as a serious disease although treatment with cyclosporine (CSA) has improved outcome. However, the duration of treatment in responders is unclear, and treatment of patients with genetic causes is a matter of debate. METHODS: Thirty-six patients with SRNS were studied retrospectively. Median age at presentation was 3.2 (range, 0.06-15.0) and median follow-up 15.5 years (range, 1.8-27.7), respectively; 23 (64%) had focal segmental glomerulosclerosis (FSGS) on biopsy. In 33/36 patients (92%), genetic testing was performed for at least three most common genes known to be mutated in SRNS. RESULTS: Nineteen patients (53%), especially those with minimal change nephrotic syndrome (MCNS) at initial biopsy (p < 0.002), entered complete remission with CSA monotherapy, including one patient with compound heterozygous NPHS1 and dominant ACTN4 mutation, respectively. Ten patients entered partial remission (28%, all FSGS), including two with NPHS2 mutations. Seven patients (six FSGS, one MCNS) did not respond to treatment. In 15 of 19 responders to CSA, treatment was stopped after a median of 3.1 years (range, 0.5-14) and no further relapses occurred in 11/15 (73%) patients with median follow-up of 9.7 years. CONCLUSIONS: CSA monotherapy is effective in SRNS. Discontinuation of CSA is possible in many patients with complete remission.


Assuntos
Actinina/genética , Ciclosporina/uso terapêutico , Glucocorticoides/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/genética , Rim/patologia , Proteínas de Membrana/genética , Nefrose Lipoide , Adolescente , Criança , Pré-Escolar , Feminino , Alemanha , Humanos , Imunossupressores/uso terapêutico , Lactente , Masculino , Conduta do Tratamento Medicamentoso/estatística & dados numéricos , Nefrose Lipoide/diagnóstico , Nefrose Lipoide/tratamento farmacológico , Nefrose Lipoide/genética , Farmacogenética , Indução de Remissão , Estudos Retrospectivos , Prevenção Secundária
10.
Kidney Int ; 85(4): 880-7, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24257694

RESUMO

Rare single-gene disorders cause chronic disease. However, half of the 6000 recessive single gene causes of disease are still unknown. Because recessive disease genes can illuminate, at least in part, disease pathomechanism, their identification offers direct opportunities for improved clinical management and potentially treatment. Rare diseases comprise the majority of chronic kidney disease (CKD) in children but are notoriously difficult to diagnose. Whole-exome resequencing facilitates identification of recessive disease genes. However, its utility is impeded by the large number of genetic variants detected. We here overcome this limitation by combining homozygosity mapping with whole-exome resequencing in 10 sib pairs with a nephronophthisis-related ciliopathy, which represents the most frequent genetic cause of CKD in the first three decades of life. In 7 of 10 sibships with a histologic or ultrasonographic diagnosis of nephronophthisis-related ciliopathy, we detect the causative gene. In six sibships, we identify mutations of known nephronophthisis-related ciliopathy genes, while in two additional sibships we found mutations in the known CKD-causing genes SLC4A1 and AGXT as phenocopies of nephronophthisis-related ciliopathy. Thus, whole-exome resequencing establishes an efficient, noninvasive approach towards early detection and causation-based diagnosis of rare kidney diseases. This approach can be extended to other rare recessive disorders, thereby providing accurate diagnosis and facilitating the study of disease mechanisms.


Assuntos
Testes Genéticos/métodos , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Adolescente , Adulto , Análise Mutacional de DNA , Diagnóstico Precoce , Exoma , Genes Recessivos , Humanos , Lactente , Masculino , Mutação , Fenótipo , Adulto Jovem
11.
Am J Physiol Renal Physiol ; 302(12): F1663-73, 2012 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-22442208

RESUMO

Interleukin-17A (IL-17) promotes inflammatory renal tissue damage in mouse models of crescentic glomerulonephritis, including murine experimental autoimmune anti-myeloperoxidase glomerulonephritis, which most likely depends on IL-17-producing Th17 cells. In human anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, however, the cellular sources of IL-17 remain to be elucidated. Therefore, we analyzed human kidney biopsies of active necrotizing and crescentic ANCA-associated glomerulonephritis by immunohistochemistry using an IL-17-specific antibody and by immunofluorescent colocalization with cell type markers. We detected numerous IL-17-expressing (IL-17(+)) cells in the glomeruli and in the tubulointerstitium. Unexpectedly, most of these IL-17(+) cells were polymorphonuclear neutrophilic granulocytes, while IL-17(+) T cells and IL-17(+) mast cells were present at significantly lower frequencies. IL-17 was not detected in other infiltrating or resident kidney cells. In those patients who had not received immunosuppressive treatment before biopsy, serum creatinine levels were positively correlated with tubulointerstitial IL-17(+) neutrophils as well as IL-17(+) T cells. Furthermore, we could demonstrate that purified human blood neutrophils expressed IL-17 protein and released it upon stimulation in vitro. In conclusion, these results support a pathogenic role for IL-17 in human ANCA-associated glomerulonephritis. Our data suggest that in the acute stage of the disease neutrophils may act as an important immediate-early innate source of IL-17 and may thereby initiate and promote ongoing renal inflammation. IL-17 may thus be a target for treating acute ANCA-associated glomerulonephritis.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/metabolismo , Glomerulonefrite/metabolismo , Interleucina-17/metabolismo , Rim/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Feminino , Glomerulonefrite/imunologia , Humanos , Rim/imunologia , Masculino , Mastócitos/imunologia , Mastócitos/metabolismo , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/metabolismo
12.
Kidney Int ; 82(7): 797-804, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22673885

RESUMO

The M-type phospholipase A2 receptor (PLA2R) is the major target antigen in idiopathic membranous nephropathy with detectable autoantibodies in the serum of up to 70% of patients. In retrospective studies, the PLA2R-autoantibody titer in the serum was sometimes negative indicating their measurement alone may be inconclusive. In order to better differentiate between primary and secondary membranous nephropathy, we conducted a prospective study that included 88 patients with a histologic diagnosis of membranous nephropathy. Immunohistochemical analysis for PLA2R was faintly positive in kidneys from normal individuals and patients with various other glomerular injuries. In 61 of the 88 patients, PLA2R expression was strongly positive in glomeruli, and in 60 of these patients PLA2R autoantibodies were also detected in the serum. The 27 patients negative for serum PLA2R autoantibodies were faintly positive for PLA2R staining in glomeruli and in 15 of these patients a secondary cause was found. The remaining 12 patients have a yet undetected secondary cause of membranous nephropathy or have different glomerular antigens other than PLA2R. Thus, increased staining for PLA2R in glomeruli of renal biopsies tightly correlates with the presence of PLA2R autoantibodies in the serum and this may help discriminate between primary and secondary membranous nephropathy.


Assuntos
Autoanticorpos/sangue , Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/imunologia , Glomérulos Renais/química , Glomérulos Renais/imunologia , Receptores da Fosfolipase A2/análise , Receptores da Fosfolipase A2/imunologia , Adulto , Idoso , Biomarcadores/sangue , Biópsia , Estudos de Casos e Controles , Creatinina/sangue , Feminino , Glomerulonefrite Membranosa/genética , Glomerulonefrite Membranosa/patologia , Humanos , Imuno-Histoquímica , Glomérulos Renais/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Proteinúria/sangue , Proteinúria/imunologia , RNA Mensageiro/análise , Receptores da Fosfolipase A2/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para Cima
13.
Am J Pathol ; 178(5): 2044-57, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21514420

RESUMO

Ubiquitin C-terminal hydrolase L1 (UCH-L1), a key protease of the ubiquitin-proteasome system (UPS), is associated with neurodegenerative diseases and cancer. Recently, de novo expression of UCH-L1 was described in podocytes in patients with membranous nephropathy (MN), in which UCH-L1 expression correlated with increased ubiquitin content. The objective of the present study was to investigate the role of UCH-L1 in ubiquitin homeostasis and proteasomal degradation in a rat model of MN. After disease induction, UCH-L1 expression increased in podocytes and coincided with decreased glomerular monoubiquitin content. After an initial increase in proteasomal activity, the UPS was impaired. In addition to an increase of ubiquitin in podocytes, aggregates were observed 1 year after disease induction, as in MN in human beings. Inhibition of UCH-L1 hydrolase function in MN reduced UPS impairment and ameliorated proteinuria. In contrast, inhibition of proteasomal activity enhanced UPS impairment, resulting in increased proteinuria. Stable UCH-L1 overexpression in cultured podocytes resulted in accumulation of monoubiquitin and polyubiquitin proteins. In contrast, stable knock-down of UCH-L1 reduced monoubiquitin and polyubiquitin proteins and significantly increased proteasomal activity, indicating that the observed effects in rat MN also occurred in cultured podocytes. These data demonstrate that UCH-L1 activity results in polyubiquitin accumulation, proteasome inhibition, and disease aggravation in experimental models of MN.


Assuntos
Glomerulonefrite Membranosa/metabolismo , Podócitos/metabolismo , Poliubiquitina/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina Tiolesterase/metabolismo , Animais , Western Blotting , Glomerulonefrite Membranosa/complicações , Glomerulonefrite Membranosa/patologia , Humanos , Imuno-Histoquímica , Masculino , Podócitos/patologia , Proteinúria/etiologia , Proteinúria/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa
14.
Case Rep Nephrol Dial ; 12(3): 226-233, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36465576

RESUMO

A 32-year-old male patient presented the clinical picture of loin pain haematuria syndrome with pain attacks accompanied by macrohaematuria. In renal biopsy, the preglomerular vessels showed segmental wall hyalinosis in the sense of low-grade nephrosclerosis, and glomerular capillaries with slightly but diffusely thickened, non-split basal membranes on electron microscopy. Notable were irregularly deformed, different dense erythrocytes in the glomerular capillaries, and several tubular lumina. The suspicion of erythrocytic enzyme deficiency could be confirmed. The enzyme activities of the erythrocytes were predominantly normal or slightly increased; only the activity of triosephosphate isomerase, a critical key enzyme of glycolysis, was reduced to 71% (resp. 57%) of the normal level, compatible with a heterozygous carrier status that could not be found. Patients with genomic triosephosphate-isomerase deficiency have degraded enzyme activities in virtually all tissues, such as leucocytes, platelets, and muscle cells. An association with neuromuscular symptoms is also known. Thus, it is possible that smooth muscle and intrarenal vascular spasms trigger clinical symptoms consisting of flank pain and phases of macrohaematuria. An aspirin-like defect (thrombocytopathy) had previously been found in connection with epistaxis (also due to TPI deficiency?). Enalapril treatment drastically reduced the frequency of macrohaematuria and pain attacks decreased to a lesser extent.

15.
Front Pediatr ; 10: 854719, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35386255

RESUMO

In West Africa, kidney diseases are frequently seen, but diagnostic and therapeutic options are poor due to limited access to specialized facilities. To unravel the etiology and develop clinical guidelines, we collected clinical data and results of kidney biopsies in 121 pediatric and mostly young adult patients with edema and proteinuria in The Gambia. Workup included clinical examination, urine and serum analysis, and kidney biopsy findings. Selected cases were treated with steroids. Results: The median age was 14.9 years (range 1.8-52.0) at presentation. The most frequent underlying histologies were post-infectious glomerulonephritis (PIGN) in 38%, focal-segmental glomerulosclerosis (FSGS) in 30%, minimal change nephrotic syndrome (MCNS) in 15%, and membranous glomerulonephritis (MGN) in 10% of cases. Patients with PIGN were significantly younger and had less proteinuria and higher serum albumin levels than the other three. Infected scabies was seen more often in cases with PIGN. Clinical parameters could not distinguish patients with FSGS, MCNS, and MGN. Steroid response was prompt in patients with MCNS (remission in 10/10 cases) compared to FSGS (4/19) and MGN (0/4). In summary, the clinical histopathological correlation allows a better approach to therapy and can be the basis for urgently needed interventional studies in steroid-resistant cases.

16.
Nephrol Dial Transplant ; 26(8): 2526-32, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21633097

RESUMO

BACKGROUND: The recent finding that phospholipase-A(2)-receptor antibodies (PLA(2)R-AB) may play a role in the development of primary membranous glomerulonephritis (MGN) offers the opportunity to measure a marker to help diagnose, classify and eventually monitor the course of patients with MGN. METHODS: We developed an immunofluorescence test, which allows the easy and specific analysis of the presence of PLA(2)R-AB in serum. The usefulness of this test was studied in 153 healthy blood donors, 90 patients with non-membranous glomerular injuries, 17 patients with a secondary form of MGN and 100 patients with biopsy-proven primary MGN. In addition, in five patients with biopsy-proven MGN, PLA(2)R-AB levels were monitored prospectively for up to 18 months following a single dose of rituximab (RTX) (375 mg/m(2) body surface). RESULTS: PLA(2)R-AB were not found in healthy controls or patients with glomerular lesions other than biopsy-proven primary MGN. Fifty-two patients with primary MGN (52%) were positive for PLA(2)R-AB. The levels ranged from 1:10 to 1:3200. In patients who had MGN and were treated with RTX the fall in PLA(2)R-AB levels was followed by a decrease in proteinuria, whereas an increase in PLA(2)R-AB levels was associated with an increase in proteinuria. CONCLUSIONS: These studies show that the new test allows the monitoring of PLA(2)R-AB levels in patients with MGN and may help in making therapeutic decisions for these patients.


Assuntos
Anticorpos/sangue , Glomerulonefrite Membranosa/diagnóstico , Proteinúria/diagnóstico , Receptores da Fosfolipase A2/imunologia , Anticorpos Monoclonais Murinos/uso terapêutico , Antineoplásicos/uso terapêutico , Estudos de Casos e Controles , Imunofluorescência , Glomerulonefrite Membranosa/complicações , Glomerulonefrite Membranosa/tratamento farmacológico , Humanos , Immunoblotting , Glomérulos Renais/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Proteinúria/tratamento farmacológico , Proteinúria/etiologia , Receptores da Fosfolipase A2/antagonistas & inibidores , Rituximab
17.
J Immunol ; 183(7): 4693-704, 2009 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-19734217

RESUMO

Infiltration of T cells into the kidney is a typical feature of human and experimental lupus nephritis that contributes to renal tissue injury. The chemokine receptor CXCR3 is highly expressed on Th1 cells and is supposed to be crucial for their trafficking into inflamed tissues. In this study, we explored the functional role of CXCR3 using the MRL/MpJ-Fas(lpr) (MRL/lpr) mouse model of systemic lupus erythematosus that closely resembles the human disease. CXCR3(-/-) mice were generated and backcrossed into the MRL/lpr background. Analysis of 20-wk-old CXCR3(-/-) MRL/lpr mice showed amelioration of nephritis with reduced glomerular tissue damage and decreased albuminuria and T cell recruitment. Most importantly, not only the numbers of renal IFN-gamma-producing Th1 cells, but also of IL-17-producing Th17 cells were significantly reduced. Unlike in inflamed kidneys, there was no reduction in the numbers of IFN-gamma- or IL-17-producing T cells in spleens, lymph nodes, or the small intestine of MRL/lpr CXCR3(-/-) mice. This observation suggests impaired trafficking of effector T cells to injured target organs, rather than the inability of CXCR3(-/-) mice to mount efficient Th1 and Th17 immune responses. These findings show a crucial role for CXCR3 in the development of experimental lupus nephritis by directing pathogenic effector T cells into the kidney. For the first time, we demonstrate a beneficial effect of CXCR3 deficiency through attenuation of both the Th1 and the newly defined Th17 immune response. Our data therefore identify the chemokine receptor CXCR3 as a promising therapeutic target in lupus nephritis.


Assuntos
Interleucina-17/fisiologia , Rim/imunologia , Rim/metabolismo , Nefrite Lúpica/imunologia , Nefrite Lúpica/metabolismo , Receptores CXCR3/fisiologia , Células Th1/imunologia , Células Th1/metabolismo , Animais , Movimento Celular/genética , Movimento Celular/imunologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Imunoglobulina G/metabolismo , Rim/patologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/genética , Nefrite Lúpica/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Camundongos Knockout , Receptores CXCR3/biossíntese , Receptores CXCR3/deficiência , Receptores CXCR3/genética , Células Th1/patologia
18.
Clin Kidney J ; 14(1): 462, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33564460

RESUMO

[This corrects the article DOI: 10.1093/ckj/sfz023.][This corrects the article DOI: 10.1093/ckj/sfz023.].

19.
J Immunol ; 181(9): 6546-56, 2008 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-18941245

RESUMO

The chemokine receptor CCR5 is predominantly expressed on monocytes and Th1-polarized T cells, and plays an important role in T cell and monocyte recruitment in inflammatory diseases. To investigate the functional role of CCR5 in renal inflammation, we induced a T cell-dependent model of glomerulonephritis (nephrotoxic serum nephritis) in CCR5(-/-) mice. Induction of nephritis in wild-type mice resulted in up-regulation of renal mRNA expression of the three CCR5 chemokine ligands, CCL5 (15-fold), CCL3 (4.9-fold), and CCL4 (3.4-fold), in the autologous phase of the disease at day 10. The up-regulated chemokine expression was paralleled by infiltration of monocytes and T cells, followed by renal tissue injury, albuminuria, and loss of renal function. Nephritic CCR5(-/-) mice showed a 3- to 4-fold increased renal expression of CCL5 (61.6-fold vs controls) and CCL3 (14.1-fold vs controls), but not of CCL4, in comparison with nephritic wild-type mice, which was accompanied by augmented renal T cell and monocyte recruitment and increased lethality due to uremia. Furthermore, CCR5(-/-) mice showed an increased renal Th1 response, whereas their systemic humoral and cellular immune responses were unaltered. Because the CCR5 ligands CCL5 and CCL3 also act via CCR1, we investigated the effects of the pharmacological CCR1 antagonist BX471. CCR1 blockade in CCR5(-/-) mice significantly reduced renal chemokine expression, T cell infiltration, and glomerular crescent formation, indicating that increased renal leukocyte recruitment and consecutive tissue damage in nephritic CCR5(-/-) mice depended on functional CCR1. In conclusion, this study shows that CCR5 deficiency aggravates glomerulonephritis via enhanced CCL3/CCL5-CCR1-driven renal T cell recruitment.


Assuntos
Glomerulonefrite/genética , Glomerulonefrite/imunologia , Receptores CCR5/deficiência , Receptores CCR5/genética , Animais , Quimiotaxia de Leucócito/genética , Quimiotaxia de Leucócito/imunologia , Glomerulonefrite/patologia , Soros Imunes/toxicidade , Imunoglobulina G/biossíntese , Rim/imunologia , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores CCR1/antagonistas & inibidores , Receptores CCR1/fisiologia , Ovinos , Linfócitos T/imunologia , Linfócitos T/patologia , Uremia/genética , Uremia/imunologia , Uremia/patologia
20.
Am J Physiol Renal Physiol ; 297(2): F429-39, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19458123

RESUMO

In renal tissue injury, activation of the transcription factor NF-kappaB has a central role in the induction of proinflammatory gene expression, which are involved in the development of progressive renal inflammatory disease. The function of NF-kappaB during the switch from the inflammatory process toward resolution, however, is largely unknown. Therefore, we assessed the time-dependent activation and function of NF-kappaB in two different models of acute nephritis. Our experiments demonstrate a biphasic activation of NF-kappaB in the anti-Thy-1 model of glomerulonephritis in rats and the LPS-induced nephritis in mice, with a first peak during the induction phase and a second peak during the resolution period. After induction of glomerular immune injury in rats, predominantly NF-kappaB p65/p50 heterodimer complexes are shifted to the nucleus whereas during the resolution phase predominantly p50 homodimers could be demonstrated in the nuclear compartment. In addition, we could demonstrate that p50 protein plays a pivotal role in the resolution of LPS-induced renal inflammation since NF-kappaB p50 knockout mice demonstrate significantly higher chemokine expression, prolonged renal inflammatory cell infiltration with consecutive tissue injury, and reduced survival. In conclusion, our studies indicate that NF-kappaB subunit p50 proteins have critical in vivo functions in immunologically mediated renal disease by downregulating inflammation during the resolution period.


Assuntos
Glomerulonefrite/metabolismo , Glomérulos Renais/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Nefrite/metabolismo , Transporte Ativo do Núcleo Celular , Doença Aguda , Animais , Soro Antilinfocitário , Southwestern Blotting , Células Cultivadas , Quimiocinas/metabolismo , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Glomerulonefrite/induzido quimicamente , Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Imuno-Histoquímica , Glomérulos Renais/irrigação sanguínea , Glomérulos Renais/patologia , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Subunidade p50 de NF-kappa B/deficiência , Subunidade p50 de NF-kappa B/genética , Subunidade p52 de NF-kappa B/metabolismo , Nefrite/induzido quimicamente , Nefrite/imunologia , Nefrite/patologia , Multimerização Proteica , Ratos , Ratos Wistar , Remissão Espontânea , Fatores de Tempo , Fator de Transcrição RelA/metabolismo , Fator de Transcrição RelB/metabolismo
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