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1.
Kidney Int ; 105(3): 593-607, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38143038

ABSTRACT

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.


Subject(s)
Apolipoprotein L1 , Renal Insufficiency, Chronic , Adult , Child , Humans , Apolipoprotein L1/genetics , Genotype , Kidney/pathology , Renal Insufficiency, Chronic/epidemiology , Renal Insufficiency, Chronic/genetics , Renal Insufficiency, Chronic/pathology , Risk Factors , Adolescent , Young Adult
2.
Lancet Reg Health Am ; 11: 100243, 2022 Jul.
Article in English | MEDLINE | ID: mdl-35378952

ABSTRACT

Background: Previous Randomised controlled trials (RCT) evaluating chloroquine and hydroxychloroquine in non-hospitalised COVID-19 patients have found no significant difference in hospitalisation rates. However, low statistical power precluded definitive answers. Methods: We conducted a multicenter, double-blind, RCT in 56 Brazilian sites. Adults with suspected or confirmed COVID-19 presenting with mild or moderate symptoms with ≤ 07 days prior to enrollment and at least one risk factor for clinical deterioration were randomised (1:1) to receive hydroxychloroquine 400 mg twice a day (BID) in the first day, 400 mg once daily (OD) thereafter for a total of seven days, or matching placebo. The primary outcome was hospitalisation due to COVID-19 at 30 days, which was assessed by an adjudication committee masked to treatment allocation and following the intention-to-treat (ITT) principle. An additional analysis was performed only in participants with SARS-CoV-2 infection confirmed by molecular or serology testing (modified ITT [mITT] analysis). This trial was registered at ClinicalTrials.gov, NCT04466540. Findings: From May 12, 2020 to July 07, 2021, 1372 patients were randomly allocated to hydroxychloroquine or placebo. There was no significant difference in the risk of hospitalisation between hydroxychloroquine and placebo groups (44/689 [6·4%] and 57/683 [8·3%], RR 0·77 [95% CI 0·52-1·12], respectively, p=0·16), and similar results were found in the mITT analysis with 43/478 [9·0%] and 55/471 [11·7%] events, RR 0·77 [95% CI 0·53-1·12)], respectively, p=0·17. To further complement our data, we conducted a meta-analysis which suggested no significant benefit of hydroxychloroquine in reducing hospitalisation among patients with positive testing (69/1222 [5·6%], and 88/1186 [7·4%]; RR 0·77 [95% CI 0·57-1·04]). Interpretation: In outpatients with mild or moderate forms of COVID-19, the use of hydroxychloroquine did not reduce the risk of hospitalisation compared to the placebo control. Our findings do not support the routine use of hydroxychloroquine for treatment of COVID-19 in the outpatient setting. Funding: COALITION COVID-19 Brazil and EMS.

5.
PLoS Negl Trop Dis ; 14(10): e0008582, 2020 10.
Article in English | MEDLINE | ID: mdl-33119586

ABSTRACT

BACKGROUND: Schistosoma mansoni schistosomiasis (SM) remains a public health problem in Brazil. Renal involvement is classically manifested as a glomerulopathy, most often membranoproliferative glomerulonephritis or focal and segmental glomerulosclerosis. We report a case of collapsing glomerulopathy (CG) associated with SM and high-risk APOL1 genotype (HRG). CASE REPORT: A 35-year-old male was admitted for hypertension and an eight-month history of lower-limb edema, foamy urine, and increased abdominal girth. He had a recent diagnosis of hepatosplenic SM, treated with praziquantel, without clinical improvement. Laboratory tests revealed serum creatinine 1.89mg/dL, blood urea nitrogen (BUN) 24mg/dL, albumin 1.9g/dL, cholesterol 531mg/dL, low-density lipoprotein 426mg/dL, platelets 115000/mm3, normal C3/C4, antinuclear antibody (ANA), rheumatoid factor (RF), and antineutrophil cytoplasmic antibodies (ANCA), negative serologies for hepatitis C virus (HCV) and human immunodeficiency virus (HIV), HBsAg negative and AntiHBc IgG positive, no hematuria or leukocyturia, 24 hour proteinuria 6.56g and negative serum and urinary immunofixation. Kidney biopsy established the diagnosis of CG. A treatment with prednisone was started without therapeutic response, progressing to end-stage kidney disease 19 months later. Molecular genetics investigation revealed an HRG. CONCLUSIONS: This is the first report of CG associated with SM in the setting of an HRG. This case highlights the two-hit model as a mechanism for CG pathogenesis, where the high-risk APOL1 genotype exerts a susceptibility role and SM infection serves as a trigger to CG.


Subject(s)
Apolipoprotein L1/genetics , Kidney Failure, Chronic/complications , Kidney Glomerulus/pathology , Schistosomiasis mansoni/complications , Schistosomiasis mansoni/pathology , Adult , Animals , Brazil , Humans , Male , Schistosoma mansoni , Schistosomiasis mansoni/genetics
7.
Am J Kidney Dis ; 72(3): 457-461, 2018 09.
Article in English | MEDLINE | ID: mdl-29548779

ABSTRACT

Primary tumoral calcinosis is a rare autosomal recessive disorder characterized by ectopic calcified tumoral masses. Mutations in 3 genes (GALNT3, FGF23, and KL) have been linked to this human disorder. We describe a case of a 28-year-old man with a history of painful firm masses over his right and left gluteal region, right clavicle region, knees, and left elbow. Biochemical analysis disclosed hyperphosphatemia (phosphate, 9.0 mg/dL) and normocalcemia (calcium, 4.8 mg/dL), with normal kidney function and fractional excretion of phosphate of 3%. Parathyroid hormone was suppressed (15 pg/mL), associated with a low-normal 25-hydroxyvitamin D (26 ng/mL) concentration but high 1,25-dihydroxyvitamin D concentration (92 pg/mL). Serum intact FGF-23 (fibroblast growth factor 23) was undetectable. Genetic analysis revealed tumoral calcinosis due to a compound heterozygous mutation in FGF23, c.201G>C (p.Gln67His) and c.466C>T (p.Gln156*). Due to lack of other treatment options and because the patient was facing severe vascular complications, we initiated a daily hemodialysis program even in the setting of normal kidney function. This unusual therapeutic option successful controlled hyperphosphatemia and reduced metastatic tumoral lesions. This is a report of a new mutation in FGF23 in which dialysis was an effective treatment option for tumoral calcinosis with normal kidney function.


Subject(s)
Calcinosis/genetics , Calcinosis/therapy , Fibroblast Growth Factors/genetics , Hyperostosis, Cortical, Congenital/genetics , Hyperostosis, Cortical, Congenital/therapy , Hyperphosphatemia/genetics , Hyperphosphatemia/therapy , Kidney/physiology , Mutation/genetics , Renal Dialysis , Adult , Calcinosis/diagnostic imaging , Fibroblast Growth Factor-23 , Humans , Hyperostosis, Cortical, Congenital/diagnostic imaging , Hyperphosphatemia/diagnostic imaging , Male , Renal Dialysis/methods , Treatment Outcome
8.
Urology ; 112: e3-e4, 2018 Feb.
Article in English | MEDLINE | ID: mdl-29154983

ABSTRACT

Renal angiomyolipomas (AMLs) are benign tumors with higher prevalence in women. Female hormones have been shown to induce AML enlargement. This case refers to a 40-year-old woman with 4 left kidney AMLs, the larger ones with 1.0 and 1.3 cm. Ten months after ovarian stimulation for egg harvesting, a computed tomography revealed an 18-cm AML with large-caliber vessels. Given her high risk of AML bleeding, the patient was submitted to selective arterial embolization, which turned out unsuccessful, supporting a plan of nephron-sparing surgery. Our case highlights the pro-growth effects of female hormones on AML, with particular emphasis to ovarian stimulation.


Subject(s)
Angiomyolipoma/etiology , Kidney Neoplasms/etiology , Ovulation Induction/adverse effects , Adult , Angiomyolipoma/pathology , Female , Humans , Kidney Neoplasms/pathology , Tumor Burden
9.
Nephron ; 136(2): 158-162, 2017.
Article in English | MEDLINE | ID: mdl-28245485

ABSTRACT

Alport syndrome (AS) is a disorder of collagen IV, a component of glomerular basement membrane (GBM). The association of AS and immunocomplex nephropathies is uncommon. This is a case of a 37-year-old woman with family history of X-linked AS, including 4 affected sons. This patient developed full-blown nephrotic syndrome along a 3-month period, a presentation not consistent with AS progression. This scenario suggested an alternative diagnosis. A kidney biopsy was therefore performed, showing membranous nephropathy (MN) in addition to GBM structural alterations compatible with AS. Whole exome sequencing also confirmed the diagnosis of X-linked AS, revealing a heterozygous pathogenic mutation in COL4A5. While a negative serum anti-phospholipase A2 receptor did not rule out a primary form of MN, it was also uncertain whether positive serologic tests for syphilis could represent a secondary factor. It is currently unknown whether this unusual association represents AS susceptibility to immunocomplex-mediated diseases or simply an association of 2 disorders.


Subject(s)
Glomerulonephritis, Membranous/complications , Nephritis, Hereditary/complications , Adult , Collagen Type IV/genetics , Disease Progression , Disease Susceptibility , Exome , Female , Glomerulonephritis, Membranous/genetics , Glomerulonephritis, Membranous/pathology , Humans , Kidney/pathology , Mutation , Nephritis, Hereditary/genetics , Nephritis, Hereditary/pathology , Nephrotic Syndrome/etiology , Nephrotic Syndrome/genetics , Pedigree
10.
J Clin Sleep Med ; 13(1): 89-94, 2017 01 15.
Article in English | MEDLINE | ID: mdl-28173916

ABSTRACT

STUDY OBJECTIVES: Restless legs syndrome (RLS) is a highly prevalent sleep disease among patients on hemodialysis. The physiopathology is still unclear, and may be multifactorial. Because of the association between iron metabolism and chronic kidney disease-mineral and bone disorders (CKD-MBD), we hypothesized that both factors would be associated with RLS. METHODS: We have evaluated hemodialysis patients, in a face-to-face interview for the diagnosis and severity of RLS, as measured by the International Restless Legs Syndrome Study Group. Clinical, demographic, and biochemical characteristics were measured. RESULTS: Out of 101 adult patients included, RLS was found in 29 (28.7%). Adjusted multinomial regression analysis revealed that age older than 35 years, transferrin saturation less than 47%, serum ferritin level less than 700 ng/mL, hemoglobin level less than 9.8 g/dL, serum phosphate level higher than 5.2 mg/dL, FGF-23 higher than 2,000 RU/mL, and C-reactive protein less than 1.24 mg/dL were independently associated with RLS. RLS was classified as mild, moderate, severe, and very severe in 3.4%, 41.7%, 44.8%, and 10.1% of patients, respectively. Scores of severity correlated significantly with erythropoietin dose/kg/w (p = 0.046), phosphate (p = 0.003), and inversely with serum albumin (p = 0.003) and calcium (p = 0.008). Phosphate and 25(OH)-vitamin D correlated with transferrin saturation. Patients with severe/very severe symptoms were mostly women, presented with lower serum iron, ionic calcium, and serum albumin levels and higher levels of serum phosphate, and higher percentage of 25(OH)-vitamin D deficiency and levels of FGF-23 higher than 2,000 RU/mL than did those with mild/moderate symptoms. CONCLUSIONS: CKD-MBD factors besides iron metabolism are associated with RLS in patients on hemodialysis, providing new insights into the understanding of RLS in this population.


Subject(s)
Chronic Kidney Disease-Mineral and Bone Disorder/complications , Chronic Kidney Disease-Mineral and Bone Disorder/metabolism , Renal Dialysis , Restless Legs Syndrome/complications , Restless Legs Syndrome/metabolism , Female , Fibroblast Growth Factor-23 , Humans , Male , Middle Aged , Minerals/metabolism , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/therapy , Severity of Illness Index
13.
J Clin Med Res ; 7(9): 724-5, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26251690

ABSTRACT

Patients with end-stage renal disease (ESRD) on dialysis have poor overall survival, and cardiovascular (CV) is the main cause of mortality among these patients. Coronary calcification is an independent predictor of mortality and CV events in dialysis patients and can be accessed by using a computerized tomography scanning. The high cost of this procedure, however, precludes routine implementation of this method for the purposes of risk stratification. Aortic arch calcification has been associated with CV mortality in the general population. Also, vascular calcification beyond the thoracic aorta has been shown to be associated with mortality in ESRD patients. We presented here a case of a young patient with ESRD in which the coronary calcification could be cleared seen through simple chest radiography. This is a 35-year-old man with a history of ESRD secondary to pyelonephritis, who was receiving conventional hemodialysis thrice a week for the last 5 years. He was submitted to chest radiography as part of routine annual cardiac screening. His blood pressure was within the target limits, although much higher in lower limbs, generating a high ankle brachial index of 1.3. He also had secondary hyperparathyroidism. His physical examination was unremarkable, except for the presence of non-functioning arteriovenous fistulas in both arms and a central venous catheter. The last routine blood test showed calcium 9.0 mg/dL, phosphate 5.7 mg/dL, potassium 4.7 mEq/L, creatinine 7.4 mg/dL, alkaline phosphatase 175 U/L, and parathyroid hormone 1,745 pg/mL. Surprisingly, the chest radiography revealed a calcified aortic valve and a calcified coronary artery. This patient had sudden cardiac death few months after this radiography had been taken. We present here a case of coronary calcification that can be seen through simple chest radiography. Such images are not usually seen, although the risk of vascular calcification is high in this population, and is closely related to CV risk. Chest radiographs, nearly universally available provide a method for assessing coronary artery calcification. Such a finding is intriguing and should alert nephrologists and cardiologists for the high risk of CV death in these patients.

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