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BACKGROUND: The identification of complement defects as major drivers of primary atypical hemolytic uremic syndrome (HUS) has transformed the landscape of thrombotic microangiopathies (TMAs), leading to the development of targeted therapies and better patient outcomes. By contrast, little is known about the presentation, genetics, and outcomes of TMA associated with specific diseases or conditions, also referred to as secondary TMA. METHODS: In this study, we assessed the relative incidence, clinical and genetic spectra, and long-term outcomes of secondary TMA versus other TMAs in consecutive patients hospitalized with a first episode of TMA from 2009 to 2019 at two European reference centers. RESULTS: During the study period, 336 patients were hospitalized with a first episode of TMA. Etiologies included atypical HUS in 49 patients (15%), thrombotic thrombocytopenic purpura (TTP) in 29 (9%), shigatoxin-associated HUS in 70 (21%), and secondary TMA in 188 (56%). The main causes of secondary TMA were hematopoietic stem-cell transplantation ( n =56, 30%), solid-organ transplantation ( n =44, 23%), and malignant hypertension ( n =25, 13%). Rare variants in complement genes were identified in 32 of 49 patients (65%) with atypical HUS and eight of 64 patients (13%) with secondary TMA; pathogenic or likely pathogenic variants were found in 24 of 49 (49%) and two of 64 (3%) of them, respectively ( P < 0.001). After a median follow-up of 1157 days, death or kidney failure occurred in 14 (29%), eight (28%), five (7%), and 121 (64%) patients with atypical HUS, TTP, shigatoxin-associated HUS, and secondary TMA, respectively. Unadjusted and adjusted Cox regressions showed that patients with secondary TMA had the highest risk of death or kidney failure (unadjusted hazard ratio [HR], 3.35; 95% confidence interval [CI], 1.85 to 6.07; P < 0.001; adjusted HR, 4.11; 95% CI, 2.00 to 8.46; P < 0.001; considering atypical HUS as reference). CONCLUSIONS: Secondary TMAs represent the main cause of TMA and are independently associated with a high risk of death and progression to kidney failure.
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The kidney is commonly involved in multiple myeloma and other disorders producing monoclonal immunoglobulins. Crystalglobulinemia is a rare condition characterized by spontaneous crystallization and deposition of monoclonal immunoglobulins within the microvasculature of the kidney and other organs, leading to inflammation, ischemia, and end-organ damage. The present case and literature review highlight the clinical spectrum, diagnostic challenges, management, and outcomes of this underrecognized complication of monoclonal gammopathy. Crystalglobulin-associated kidney disease should be suspected in patients with rapidly progressive kidney disease associated with hematuria, proteinuria, extrarenal lesions (ie, skin and joints), and monoclonal gammopathy. Kidney biopsy is critical to the diagnosis, which relies on the identification by ultrastructural analysis of electron-dense crystalline structures composed of a monoclonal immunoglobulin within the kidney microvasculature. Conventional immunofluorescence on frozen tissue frequently fails to detect monoclonal protein deposits, and pronase-based antigen retrieval on paraffin-embedded material or immunoelectron microscopy is required to unmask antigenic epitopes located within crystalline inclusions. Early intervention combining treatment of clonal cell proliferation and plasma exchanges is warranted to reduce the burden of this rare but dramatic complication of monoclonal gammopathy.
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BACKGROUND: The severity of coronavirus disease 2019 (COVID-19) is highly variable between individuals, ranging from asymptomatic infection to critical disease with acute respiratory distress syndrome requiring mechanical ventilation. Such variability stresses the need for novel biomarkers associated with disease outcome. As SARS-CoV-2 infection causes a kidney proximal tubule dysfunction with urinary loss of uric acid, we hypothesized that low serum levels of uric acid (hypouricemia) may be associated with severity and outcome of COVID-19. METHODS: In a retrospective study using two independent cohorts, we investigated and validated the prevalence, kinetics and clinical correlates of hypouricemia among patients hospitalized with COVID-19 to a large academic hospital in Brussels, Belgium. Survival analyses using Cox regression and a competing risk approach assessed the time to mechanical ventilation and/or death. Confocal microscopy assessed the expression of urate transporter URAT1 in kidney proximal tubule cells from patients who died from COVID-19. RESULTS: The discovery and validation cohorts included 192 and 325 patients hospitalized with COVID-19, respectively. Out of the 517 patients, 274 (53%) had severe and 92 (18%) critical COVID-19. In both cohorts, the prevalence of hypouricemia increased from 6% upon admission to 20% within the first days of hospitalization for COVID-19, contrasting with a very rare occurrence (< 1%) before hospitalization for COVID-19. During a median (interquartile range) follow-up of 148 days (50-168), 61 (12%) patients required mechanical ventilation and 93 (18%) died. In both cohorts considered separately and in pooled analyses, low serum levels of uric acid were strongly associated with disease severity (linear trend, P < 0.001) and with progression to death and respiratory failure requiring mechanical ventilation in Cox (adjusted hazard ratio 5.3, 95% confidence interval 3.6-7.8, P < 0.001) or competing risks (adjusted hazard ratio 20.8, 95% confidence interval 10.4-41.4, P < 0.001) models. At the structural level, kidneys from patients with COVID-19 showed a major reduction in urate transporter URAT1 expression in the brush border of proximal tubules. CONCLUSIONS: Among patients with COVID-19 requiring hospitalization, low serum levels of uric acid are common and associate with disease severity and with progression to respiratory failure requiring invasive mechanical ventilation.
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COVID-19/metabolismo , COVID-19/fisiopatologia , Túbulos Renais Proximais/metabolismo , Índice de Gravidade de Doença , Ácido Úrico/sangue , Idoso , Bélgica , COVID-19/complicações , Estudos de Coortes , Estado Terminal/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Avaliação de Resultados em Cuidados de Saúde , Estudos RetrospectivosRESUMO
BACKGROUND: Membranous nephropathy (MN) results from deposition of antigen-antibody complexes along the glomerular basement membrane (GBM). PLA2R, THSD7A, NELL1, and SEMA3B account for 80%-90% of target antigens in MN. METHODS: We performed laser microdissection and mass spectrometry (MS/MS) in kidney biopsies from 135 individuals with PLA2R-negative MN, and used immunohistochemistry/immunofluorescence and confocal microscopy to confirm the MS/MS finding, detect additional cases, and localize the novel protein. We also performed MS/MS and immunohistochemistry on 116 controls and used immunofluorescence microscopy to screen biopsy samples from two validation cohorts. Western blot and elution studies were performed to detect antibodies in serum and biopsy tissue. RESULTS: MS/MS studies detected a unique protein, protocadherin 7 (PCDH7), in glomeruli of ten (5.7%) PLA2R-negative MN cases, which also were negative for PLA2R, THSD7A, EXT1/EXT2, NELL1, and SEMA3B. Spectral counts ranged from six to 24 (average 13.2 [SD 6.6]). MS/MS did not detect PCDH7 in controls (which included 28 PLA2R-positive cases). In all ten PCDH7-positive cases, immunohistochemistry showed bright granular staining along the GBM, which was absent in the remaining cases of PLA2R-negative MN and control cases. Four of 69 (5.8%) cases in the validation cohorts (all of which were negative for PLA2R, THSD7A, EXT1, NELL1, and SEMA3B) were PCDH7-positive MN. Kidney biopsy showed minimal complement deposition in 12 of the 14 PCDH7-associated cases. Confocal microscopy showed colocalization of PCDH7 and IgG along the GBM. Western blot analysis using sera from six patients showed antibodies to nonreduced PCDH7. Elution of IgG from frozen tissue of PCDH7-associated MN showed reactivity against PCDH7. CONCLUSIONS: MN associated with the protocadherin PCDH7 appears to be a distinct, previously unidentified type of MN.
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Caderinas/metabolismo , Glomerulonefrite Membranosa/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Glomerulonefrite Membranosa/patologia , Humanos , Microdissecção e Captura a Laser , Masculino , Espectrometria de Massas , Microscopia Confocal , Pessoa de Meia-Idade , ProtocaderinasRESUMO
Background: Pneumocystis jirovecii associated pneumonia is a potentially life-threatening opportunistic infection, occurring most frequently in the first year after renal transplantation, and may be associated with hypercalcemia. Clinical presentation:We report the case of a renal transplant recipient presenting with Pneumocystis jirovecii associated pneumonia and hypercalcemia due to ectopic production of 1,25-dihydroxyvitamin D, 6 years after renal transplantation. Calcemia and 1-25 hydroxyvitamin D levels normalized after our patient was treated by trimethoprim-sulfamethoxazole. Discussion: We review similar cases to delineate the clinical and biological profile of patients with Pneumocystis jirovecii pneumonia associated hypercalcemia. Conclusion:Physicians should evoke this diagnosis in renal transplant recipients presenting with pulmonary infection associated with hypercalcemia.
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Hipercalcemia , Transplante de Rim/efeitos adversos , Pneumocystis carinii , Pneumonia por Pneumocystis , Feminino , Humanos , Hipercalcemia/diagnóstico , Hipercalcemia/etiologia , Pulmão/diagnóstico por imagem , Pulmão/patologia , Pessoa de Meia-Idade , Vitamina D/análogos & derivados , Vitamina D/metabolismoRESUMO
BACKGROUND: Oxalate nephropathy is a potentially underestimated cause of kidney failure characterized by massive deposition of calcium oxalate crystals in the renal parenchyma. The prevalence and modes of presentation of this entity are ill-defined. METHODS: Here we report on the largest consecutive series of cases of adult oxalate nephropathy diagnosed on native kidney biopsies from January 2010 to December 2018 in the UCLouvain Kidney Disease Network. RESULTS: We screened 2265 native kidney biopsies and identified 22 cases (1%) of oxalate nephropathy. Patients had a mean age at diagnosis of 61 years (±20) and presented either with acute on chronic kidney disease (CKD) (62%) or with acute kidney injury (AKI) (38%). Mean serum creatinine at biopsy was 8.0 ± 4.5 mg/dl. Kidney biopsies showed abundant calcium oxalate crystal deposits, associated with acute interstitial nephritis and tubular necrosis, and variable degrees of interstitial fibrosis and tubular atrophy. Chronic pancreatitis and gastric bypass were the most common causes of oxalate nephropathy (48%). During a mean follow-up of 29 months, half of the patients (52%) progressed to kidney failure, all within the month following diagnosis. Higher serum creatinine level at presentation and interstitial fibrosis and tubular atrophy score were associated with progression to kidney failure. CONCLUSION: Oxalate nephropathy is the cause of kidney disease in 1% of consecutive native kidney biopsies and typically presents as acute on CKD or AKI. The prognosis of the disease is poor, with a high rate of kidney failure within the first month after the diagnosis.
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RATIONALE & OBJECTIVE: Membranous nephropathy (MN) is characterized by the deposition of immune complexes along glomerular basement membranes. M-Type phospholipase A2 receptor (PLA2R), thrombospondin type 1 domain-containing 7A (THSD7A), exostosin 1 and 2 (EXT1/2), and neural epidermal growth factor-like 1 protein (NELL-1) have been identified as established or potential podocyte antigens in MN. We investigated the association of podocyte antigen staining with MN clinical phenotype and outcomes. STUDY DESIGN: Multicenter retrospective cohort study. SETTING & PARTICIPANTS: 177 consecutive patients with MN unrelated to lupus erythematosus, identified after screening of 3,875 native kidney biopsies performed in the Belgian UCLouvain Kidney Disease Network from 2000 through 2018. PREDICTOR: Positive immunostaining for podocyte antigens on archived kidney biopsy samples. OUTCOMES: Association with different phenotypes (baseline characteristics of patients and pathologic findings on kidney biopsy), time to cancer and to kidney failure. ANALYTICAL APPROACH: Kaplan-Meier estimates and Cox regression analyses to assess time to cancer and kidney failure. RESULTS: 177 patients were followed up for a median of 4.0 (IQR, 1.3-8.0) years. Diagnosis of PLA2R-positive (PLA2R+), THSD7A+, and double-negative (PLA2R-/THSD7A-) MN was made in 117 (66.1%), 6 (3.4%), and 54 (30.5%) patients, respectively. Progression to kidney failure was similar in all groups. Although the number of patients with THSD7A+MN was small, they showed a higher incidence (50%) and increased risk for developing cancer during follow-up (adjusted HR, 5.0 [95% CI, 1.4-17.9]; P=0.01). 8% and 5% of patients with double-negative MN stained positively for EXT1/2 and NELL-1, respectively. Most patients with EXT1/2+MN were women, had features of systemic autoimmunity, and showed glomerular C1q deposits. LIMITATIONS: Retrospective design; small number of patients in the THSD7A group; lack of evaluation of immunoglobulin G subclasses deposition. CONCLUSIONS: Our real-world data describe the relative prevalence of subgroups of MN and support the hypothesis that a novel classification of MN based on podocyte antigen staining may be clinically relevant.
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Autoanticorpos/imunologia , Glomerulonefrite Membranosa/imunologia , Podócitos/patologia , Adulto , Idoso , Biópsia , Progressão da Doença , Feminino , Seguimentos , Glomerulonefrite Membranosa/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Podócitos/imunologia , Estudos Retrospectivos , Coloração e Rotulagem/métodosRESUMO
Membranous nephropathy is characterized by deposition of immune complexes along the glomerular basement membrane. PLA2R and THSD7A are target antigens in 70% and 1-5% of primary membranous nephropathy cases, respectively. In the remaining cases, the target antigen is unknown. Here, laser microdissection of glomeruli followed by mass spectrometry was used to identify novel antigen(s) in PLA2R-negative membranous nephropathy. An initial pilot mass spectrometry study in 35 cases of PLA2R-negative membranous nephropathy showed high spectral counts for neural tissue encoding protein with EGF-like repeats, NELL-1, in six cases. Mass spectrometry failed to detect NELL-1 in 23 PLA2R-associated membranous nephropathy and 88 controls. NELL-1 was localized by immunohistochemistry, which showed bright granular glomerular basement membrane staining for NELL-1 in all six cases. Next, an additional 23 NELL-1 positive cases of membranous nephropathy were identified by immunohistochemistry in a discovery cohort of 91 PLA2R-negative membranous nephropathy cases, 14 were confirmed by mass spectrometry. Thus, 29 of 126 PLA2R-negative cases were positive for NELL-1. PLA2R-associated membranous nephropathy and controls stained negative for NELL-1. We then identified five NELL-1 positive cases of membranous nephropathy out of 84 PLA2R and THSD7A-negative cases in two validation cohorts from France and Belgium. By confocal microscopy, both IgG and NELL-1 co-localized to the glomerular basement membrane. Western blot analysis showed reactivity to NELL-1 in five available sera, but no reactivity in control sera. Clinical and biopsy findings of NELL-1 positive membranous nephropathy showed features of primary membranous nephropathy. Thus, a subset of membranous nephropathy is associated with accumulation and co-localization of NELL-1 and IgG along the glomerular basement membrane, and with anti-NELL-1 antibodies in the serum. Hence, NELL-1 defines a distinct type of primary membranous nephropathy.
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Autoantígenos/imunologia , Proteínas de Ligação ao Cálcio/imunologia , Membrana Basal Glomerular/patologia , Glomerulonefrite Membranosa/imunologia , Idoso , Autoanticorpos/análise , Autoanticorpos/sangue , Autoanticorpos/imunologia , Autoantígenos/análise , Biópsia , Proteínas de Ligação ao Cálcio/análise , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Membrana Basal Glomerular/imunologia , Membrana Basal Glomerular/ultraestrutura , Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/diagnóstico , Glomerulonefrite Membranosa/patologia , Humanos , Microdissecção e Captura a Laser , Masculino , Espectrometria de Massas , Microscopia Confocal , Microscopia Eletrônica , Microscopia de Fluorescência , Pessoa de Meia-Idade , Projetos Piloto , Receptores da Fosfolipase A2/análise , Receptores da Fosfolipase A2/imunologia , Trombospondinas/análise , Trombospondinas/imunologiaRESUMO
Hypertensive emergency can cause thrombotic microangiopathy (TMA) in the kidneys with high rates of end-stage renal disease (ESRD) and vice versa. The conundrum of hypertension as the cause of TMA or consequence of TMA on the background of defects in complement regulation remains difficult. Patients with hypertensive emergency and TMA on kidney biopsy were tested for ex vivo C5b9 formation on the endothelium and rare variants in complement genes to identify complement-mediated TMA. We identified factors associated with defects in complement regulation and poor renal outcomes. Massive ex vivo C5b9 formation was found on resting endothelial cells in 18 (69%) out of 26 cases at the presentation, including the 9 patients who carried at least one rare genetic variant. Thirteen (72%, N=18) and 3 (38%, N=8) patients with massive and normal ex vivo complement activation, respectively, progressed to ESRD (P=0.03). In contrast to BP control, inhibition of C5 activation prevented ESRD to occur in 5 (83%, N=6) patients with massive ex vivo complement activation. TMA-related graft failure occurred in 7 (47%, N=15) donor kidneys and was linked to genetic variants. The assessment of both ex vivo C5b9 formation and screening for rare variants in complement genes may categorize patients with hypertensive emergency and TMA into different groups with potential therapeutic and prognostic implications. We propose an algorithm to recognize patients at the highest risk for defects in complement regulation.
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Pressão Sanguínea/fisiologia , Ativação do Complemento/fisiologia , Proteínas do Sistema Complemento/metabolismo , Emergências , Hipertensão Maligna/complicações , Rim/patologia , Microangiopatias Trombóticas/diagnóstico , Adulto , Biópsia , Células Endoteliais/patologia , Feminino , Humanos , Hipertensão Maligna/diagnóstico , Falência Renal Crônica/complicações , Falência Renal Crônica/diagnóstico , Masculino , Prognóstico , Reprodutibilidade dos Testes , Fatores de Risco , Microangiopatias Trombóticas/etiologia , Microangiopatias Trombóticas/metabolismoRESUMO
Sneddon's syndrome is a rare, noninflammatory thrombotic vasculopathy characterized by the combination of livedo racemosa, recurrent stroke, and histopathological skin lesions of endarteritis obliterans. Although multiorgan involvement suggests its systemic nature, detailed pathological description of affected organs - including the kidney - is exceptional. We report a case of Sneddon's syndrome with chronic kidney disease, associated with features of endarteritis obliterans in the skin and the kidney. The clinical presentation of our patient is compared to previously reported cases of Sneddon's syndrome with biopsy-proven kidney disease. We also discuss the differential diagnosis, pathophysiological mechanisms, relationship with antiphospholipid syndrome, and management of patients with Sneddon's syndrome and kidney disease. This clinical observation supports the systemic nature of Sneddon's syndrome and provides insights into the mechanisms by which this rare but probably underdiagnosed disease alters kidney function.â©.
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Insuficiência Renal Crônica/etiologia , Síndrome de Sneddon/complicações , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
Despite optimal anticoagulation and blood pressure control, patients with antiphospholipid syndrome (APS) nephropathy frequently progress to kidney failure, and recurrence after transplantation is common. The mTORC (mechanistic target of rapamycin complex) pathway was recently identified as a potential intermediate and a therapeutic target in vascular lesions associated with APS nephropathy. However, these results were derived from the retrospective analysis of a small cohort of patients receiving sirolimus after kidney transplantation. Therefore, they warranted external validation and the demonstration of the potential benefit of sirolimus in native kidney APS nephropathy. We report a patient with active APS nephropathy lesions occurring on native kidneys, in which endothelial mTORC activation was substantiated at the molecular level. Treatment with sirolimus was shown on a repeat kidney biopsy to successfully inhibit the AKT/mTORC pathway and was associated with significant improvement in kidney function and lesions of vasculopathy. Drug tolerance was excellent during the entire follow-up. This case validates and extends previous observations in kidney transplant recipients and demonstrates that endothelial activation of the AKT/mTORC pathway occurs in the damaged renal vasculature of native kidneys in APS nephropathy. These findings further support the potential of precision medicine and the use of mTORC activation as a biomarker of disease activity and as therapeutic target in patients with APS nephropathy.
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Síndrome Antifosfolipídica/tratamento farmacológico , Imunossupressores/uso terapêutico , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adulto , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anticoagulantes/uso terapêutico , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/metabolismo , Feminino , Humanos , Microscopia Confocal , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ramipril/uso terapêutico , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Proteína S6 Ribossômica/metabolismo , Transdução de Sinais , Microangiopatias Trombóticas/etiologia , Microangiopatias Trombóticas/metabolismo , Microangiopatias Trombóticas/patologia , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVES: Atypical hemolytic uremic syndrome is a form of thrombotic microangiopathy caused by dysregulation of the alternative complement pathway. There is evidence showing complement activation in other thrombotic microangiopathies. The aim of this study was to evaluate complement activation in different thrombotic microangiopathies and to monitor treatment response. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Complement activation was assessed by exposing endothelial cells to sera or activated-patient plasma-citrated plasma mixed with a control sera pool (1:1)-to analyze C5b-9 deposits by immunofluorescence. Patients with atypical hemolytic uremic syndrome (n=34) at different stages of the disease, HELLP syndrome (a pregnancy complication characterized by hemolysis, elevated liver enzymes, and low platelet count) or severe preeclampsia (n=10), and malignant hypertension (n=5) were included. RESULTS: Acute phase atypical hemolytic uremic syndrome-activated plasma induced an increased C5b-9 deposition on endothelial cells. Standard and lower doses of eculizumab inhibited C5b-9 deposition in all patients with atypical hemolytic uremic syndrome, except in two who showed partial remission and clinical relapse. Significant fibrin formation was observed together with C5b-9 deposition. Results obtained using activated-plasma samples were more marked and reproducible than those obtained with sera. C5b-9 deposition was also increased with samples from patients with HELLP (all cases) and preeclampsia (90%) at disease onset. This increase was sustained in those with HELLP after 40 days, and levels normalized in patients with both HELLP and preeclampsia after 6-9 months. Complement activation in those with malignant hypertension was at control levels. CONCLUSIONS: The proposed methodology identifies complement overactivation in patients with atypical hemolytic uremic syndrome at acute phase and in other diseases such as HELLP syndrome and preeclampsia. Moreover, it is sensitive enough to individually assess the efficiency of the C5 inhibition treatment.
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Ativação do Complemento , Microangiopatias Trombóticas/imunologia , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Síndrome Hemolítico-Urêmica Atípica/imunologia , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Feminino , Síndrome HELLP/imunologia , Humanos , Masculino , Pré-Eclâmpsia/tratamento farmacológico , Pré-Eclâmpsia/imunologia , Gravidez , Microangiopatias Trombóticas/tratamento farmacológicoRESUMO
BACKGROUND: Hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome is a rare autosomal dominant disorder, secondary to mutations in the GATA-3 gene. Due to its wide range of penetrance and expressivity, the disease may not always be recognized. We herein describe clinical and genetic features of patients with HDR syndrome, highlighting diagnostic clues. METHODS: Medical records of eight patients from five unrelated families exhibiting GATA-3 mutations were reviewed retrospectively, in conjunction with all previously reported cases. RESULTS: HDR syndrome was diagnosed in eight patients between the ages of 18 and 60 years. Sensorineural deafness was consistently diagnosed, ranging from clinical hearing loss since infancy in seven patients to deafness detected only by audiometry in adulthood in one single patient. Hypoparathyroidism was present in six patients (with hypocalcaemia and inaugural seizures in two out of six). Renal abnormalities observed in six patients were diverse and of dysplastic nature. Three patients displayed nephrotic-range proteinuria and reached end-stage renal disease (ESRD) between the ages of 19 and 61 years, whilst lesions of focal and segmental glomerulosclerosis were histologically demonstrated in one of them. Interestingly, phenotype severity differed significantly between a mother and son within one family. Five new mutations of GATA-3 were identified, including three missense mutations affecting zinc finger motifs [NM_001002295.1: c.856A>G (p.N286D) and c.1017C>G (p.C339W)] or the conserved linker region [c.896G>A (p.R299G)], and two splicing mutations (c.924+4_924+19del and c.1051-2A>G). Review of 115 previously reported cases of GATA-3 mutations showed hypoparathyroidism and deafness in 95% of patients, and renal abnormalities in only 60%. Overall, 10% of patients had reached ESRD. CONCLUSIONS: We herein expand the clinical and mutational spectrum of HDR syndrome, illustrating considerable inter- and intrafamilial phenotypic variability. Diagnosis of HDR should be considered in any patient with hypoparathyroidism and deafness, whether associated with renal abnormalities or not. HDR diagnosis is established through identification of a mutation in the GATA-3 gene.
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Surdez/diagnóstico , Fator de Transcrição GATA3/genética , Hipoparatireoidismo/diagnóstico , Rim/anormalidades , Mutação de Sentido Incorreto/genética , Anormalidades Urogenitais/diagnóstico , Adolescente , Adulto , Idoso , Surdez/genética , Feminino , Humanos , Hipoparatireoidismo/genética , Masculino , Pessoa de Meia-Idade , Linhagem , Prognóstico , Estudos Retrospectivos , Síndrome , Anormalidades Urogenitais/genética , Adulto JovemRESUMO
BACKGROUND: Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis characterized by abrupt onset of hypertension, thrombotic microangiopathy, and kidney injury. The mechanisms of the disease remain ill-defined, but a growing body of evidence suggests that activation of the complement system may be involved. METHODS: Here, we report the case of a patient presenting with severe SRC and strong evidence of complement activation, both in serum and in the kidney, in the absence of genetic defect of the complement system. RESULTS: Immunofluorescence studies on kidney biopsy showed significant deposits of C1q and C4d in the endothelium of renal arterioles, pointing toward activation of the classical pathway. Because of the dramatic clinical and histological severity, and the lack of response to early treatment with angiotensin-converting enzyme inhibitors, calcium channel blockers and plasma exchange, the patient was treated with the specific C5 blocker eculizumab.Contrarily to conventional treatment, eculizumab efficiently blocked C5b-9 deposition ex vivo and maintained hematological remission. Unfortunately, the patient died from heart failure a few weeks later. Postmortem examination of the heart showed diffuse patchy interstitial fibrosis, the typical lesion of systemic sclerosis-related cardiomyopathy, but normal coronary arteries and myocardial microvasculature. CONCLUSION: SRC may lead to complement system activation through the classical pathway. Early administration of C5 inhibitor eculizumab may have therapeutic potential in patients with life-threatening SRC refractory to conventional treatment using angiotensin-converting enzyme inhibitors.
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Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Ativação do Complemento/efeitos dos fármacos , Ativação do Complemento/imunologia , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/imunologia , Complicações na Gravidez/patologia , Gravidez Múltipla , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/imunologia , Injúria Renal Aguda/patologia , Adulto , Biópsia , Complemento C1q/análise , Complemento C4b/análise , Complemento C5/antagonistas & inibidores , Via Clássica do Complemento/efeitos dos fármacos , Via Clássica do Complemento/imunologia , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Evolução Fatal , Feminino , Humanos , Recém-Nascido , Rim/irrigação sanguínea , Rim/imunologia , Rim/patologia , Microscopia de Fluorescência , Fragmentos de Peptídeos/análise , Gravidez , Escleroderma Sistêmico/patologiaAssuntos
Anticoagulantes/efeitos adversos , Calcinose/induzido quimicamente , Hiperfosfatemia/induzido quimicamente , Nadroparina/efeitos adversos , Dermatopatias/induzido quimicamente , Pele/efeitos dos fármacos , Abdome , Adulto , Biópsia , Calcinose/diagnóstico , Quelantes/uso terapêutico , Substituição de Medicamentos , Enoxaparina/uso terapêutico , Feminino , Humanos , Hiperfosfatemia/diagnóstico , Hiperfosfatemia/tratamento farmacológico , Fatores de Risco , Sevelamer/uso terapêutico , Índice de Gravidade de Doença , Pele/patologia , Dermatopatias/diagnóstico , Tomografia Computadorizada por Raios X , Resultado do TratamentoAssuntos
Artralgia/etiologia , Hipofosfatemia/etiologia , Falência Renal Crônica/complicações , Osteomalacia/etiologia , Humanos , Falência Renal Crônica/terapia , Extremidade Inferior , Masculino , Pessoa de Meia-Idade , Osteomalacia/diagnóstico por imagem , Radiografia , Diálise Renal , Deficiência de Vitamina D/complicaçõesRESUMO
BACKGROUND: Periostin is a matricellular protein involved in tissue remodeling through the promotion of adhesion, cell survival, cellular dedifferentiation, and fibrogenesis. It can be induced by transforming growth factor beta and high glucose concentrations. We hypothesized that this protein might be expressed in the peritoneal cavity of patients on peritoneal dialysis (PD) and even more in patients with signs of encapsulating peritoneal sclerosis (EPS). METHOD: In this retrospective study, we included peritoneal biopsies from patients on PD with EPS (n = 7) and without signs of EPS (n = 10), and we compared them with biopsies taken during hernia repair from patients not on PD (n = 11) and during various procedures from uremic patients not on PD (n = 6). Periostin was localized by immunohistochemistry, scored semiquantitatively, and quantified by morphometry. Periostin protein concentrations were measured by ELISA in dialysates from 15 patients. Periostin messenger RNA was quantified in vitro in peritoneal fibroblasts. RESULTS: In control biopsies, periostin was present in the walls of larger arteries and focally in extracellular matrix in the submesothelial zone. Patients on PD demonstrated interstitial periostin in variable amounts depending on the severity of submesothelial fibrosis. In EPS, periostin expression was very prominent in the sclerosis layer. The area of periostin was significantly larger in EPS biopsies than in control biopsies, and the percentage of periostin-positive area correlated with the thickness of the submesothelial fibrosis zone. Periostin concentrations in dialysate increased significantly with time on PD in patients without signs of EPS; in patients with EPS, periostin concentrations in dialysate were low and demonstrated the smallest increase with time. In vitro, periostin was found to be strongly expressed by peritoneal fibroblasts. CONCLUSION: Periostin is strongly expressed by fibroblasts and deposited in the peritoneal cavity of patients with EPS and with simple peritoneal fibrosis on PD. This protein might play a role in the progression of peritoneal injury, and low levels of periostin after prolonged time on PD might be a marker of EPS.