Thrombomodulin gene mutation and associated predisposing factors in familial collapsing glomerulopathy.

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

Recurrence of membranous nephropathy after kidney transplantation: A multicenter retrospective cohort study.

Membranous nephropathy (MN) is a leading cause of kidney failure worldwide and frequently recurs after transplant. Available data originated from small retrospective cohort studies or registry analyses; therefore, uncertainties remain on risk factors for MN recurrence and response to therapy. Within the Post-Transplant Glomerular Disease Consortium, we conducted a retrospective multicenter cohort study examining the MN recurrence rate, risk factors, and response to treatment. This study screened 22,921 patients across 3 continents and included 194 patients who underwent a kidney transplant due to biopsy-proven MN. The cumulative incidence of MN recurrence was 31% at 10 years posttransplant. Patients with a faster progression toward end-stage kidney disease were at higher risk of developing recurrent MN (hazard ratio [HR], 0.55 per decade; 95% confidence interval [CI], 0.35-0.88). Moreover, elevated pretransplant levels of anti-phospholipase A2 receptor (PLA2R) antibodies were strongly associated with recurrence (HR, 18.58; 95% CI, 5.37-64.27). Patients receiving rituximab for MN recurrence had a higher likelihood of achieving remission than patients receiving renin-angiotensin-aldosterone system inhibition alone. In sum, MN recurs in one-third of patients posttransplant, and measurement of serum anti-PLA2R antibody levels shortly before transplant could aid in risk-stratifying patients for MN recurrence. Moreover, patients receiving rituximab had a higher rate of treatment response.

Diagnosis and management of ANCA-associated vasculitis.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis consists of two main diseases, granulomatosis with polyangiitis and microscopic polyangiitis, and remains among the most devastating and potentially lethal forms of autoimmune inflammatory disease. Granulomatosis with polyangiitis and microscopic polyangiitis are characterised by a necrotising vasculitis that can involve almost any organ, and have generally been studied together. The diseases commonly affect the kidneys, lungs, upper respiratory tract, skin, eyes, and peripheral nerves. Granulomatous inflammation and multinucleated giant cells are key pathological hallmarks of granulomatosis with polyangiitis, but are absent in microscopic polyangiitis. Many immune system events are essential to disease aetiopathogenesis, such as activation of the alternative complement pathway, neutrophil activation via complement receptors, and the influx of inflammatory cells, including monocytes and macrophages. These cells perpetuate inflammation and lead to organ damage. During the 21st century, the management of ANCA-associated vasculitis has moved away from reliance on cytotoxic medications and towards targeted biological medications for both the induction and maintenance of disease remission. Earlier diagnosis, partly the result of more reliable ANCA testing, has led to improved patient outcomes and better survival. Reductions in acute disease-related mortality have now shifted focus to long-term morbidities related to ANCA-associated vasculitis and their treatments, such as chronic kidney disease and cardiovascular disease. Therapeutic approaches in both clinical trials and clinical practice still remain too reliant on glucocorticoids, and continued efforts to reduce toxicity from glucocorticoids remain a priority in the development of new treatment strategies.

COVID-19 outcomes in patients with a history of immune-mediated glomerular diseases.

Introduction: Patients with immune-mediated glomerular diseases are considered at high risk for severe COVID-19 outcomes. However, conclusive evidence for this patient population is scarce. Methods: We created a global registry and retrospectively collected clinical data of patients with COVID-19 and a previously diagnosed immune-mediated glomerular disease to characterize specific risk factors for severe COVID-19 outcomes. Results: Fifty-nine patients with a history of immune-mediated glomerular diseases were diagnosed with COVID-19 between 01.03.2020 and 31.08.2021. Over a mean follow-up period of 24.79 ± 18.89 days, ten patients (16.9%) developed acute kidney injury. Overall, 44.1% of patients were managed in an outpatient setting and therefore considered as having "non-severe" COVID-19, while 55.9% of patients had severe COVID-19 requiring hospitalization including worse outcomes. Comparing both groups, patients with severe COVID-19 were significantly older (53.55 ± 17.91 versus 39.77 ± 14.95 years, p = .003), had lower serum albumin levels at presentation (3.00 ± 0.80 g/dL versus 3.99 ± 0.68 g/dL, p = .016) and had a higher risk of developing acute kidney injury (27% versus 4%, p = .018). Male sex (p <.001) and ongoing intake of corticosteroids at presentation (p = .047) were also significantly associated with severe COVID-19 outcomes, while the overall use of ongoing immunosuppressive agents and glomerular disease remission status showed no significant association with the severity of COVID-19 (p = .430 and p = .326, respectively). Conclusion: Older age, male sex, ongoing intake of corticosteroids and lower serum albumin levels at presentation were identified as risk factors for severe COVID-19 outcomes in patients with a history of various immune-mediated glomerular diseases.

Membranoproliferative glomerulonephritis: current histopathological classification, clinical profile, and kidney outcomes / Glomerulonefrite membranoproliferativa: classificação histopatológica atual, perfil clínico e desfechos renais

Abstract Introduction: Membranoproliferative glomerulonephritis (MPGN) is a rare glomerular disease with a variable prognosis. A new classification based on the presence or absence of immunoglobulins and complement deposits in immunofluorescence microscopy (IF) of kidney biopsy has recently been proposed. The objectives of the study were to determine and compare the clinical, laboratory, and histopathological characteristics of those with primary or secondary MPGN, reclassify the primary ones based on IF findings, and evaluate kidney outcomes. Methods: This was an observational retrospective cohort study carried out in a single center (UNIFESP), based on the data collected from medical records of patients followed from 1996 to 2019. Results: Of 53 cases of MPGN, 36 (67.9%) were classified as primary and 17 (32.1%) as secondary MPGN. Most patients were hypertensive (84.9%) and had edema (88.7%) and anemia (84.9%); 33 (91.7%) patients classified as primary MPGN were reclassified as immune-complex-mediated and 3 (8.3%) as complement-mediated. The secondary MPGN group had hematuria more frequently (p <0.001) and a higher prevalence of deposits of IgG (p = 0.02) and C1q (p = 0.003). Regarding the outcome, 39% of the patients achieved partial or complete remission. Lower initial serum albumin and higher initial 24-hour proteinuria were factors associated with worst renal prognosis. Conclusions: According to the new histological classification, the vast majority of MPGN cases were classified as being mediated by immune complexes. There were few differences between primary and secondary MPGN in relation to their clinical and laboratory characteristics.

Resumo Introdução: Glomerulonefrite membranoproliferativa (GNMP) é uma doença glomerular rara com prognóstico variável. Recentemente, foi proposta uma nova classificação baseada na presença ou ausência de imunoglobulinas e depósitos de complemento na microscopia de imunofluorescência (IF) da biópsia renal. Os objetivos do estudo foram determinar e comparar as características clínicas, laboratoriais e histopatológicas daqueles com GNMP primária ou secundária, reclassificar as primárias com base em achados da IF e avaliar os desfechos renais. Métodos: Este foi um estudo de coorte observacional retrospectivo realizado em centro único (UNIFESP), com base nos dados coletados de prontuários de pacientes acompanhados de 1996 a 2019. Resultados: Dos 53 casos de GNMP, 36 (67,9%) foram classificados como GNMP primária e 17 (32,1%) como GNMP secundária. A maioria dos pacientes era hipertensa (84,9%) e apresentava edema (88,7%) e anemia (84,9%); 33 (91,7%) pacientes classificados como GNMP primária foram reclassificados como mediados por imunocomplexo e 3 (8,3%) como mediados por complemento. O grupo de GNMP secundária apresentou mais frequentemente hematúria (p <0,001) e maior prevalência de depósitos de IgG (p = 0,02) e C1q (p = 0,003). Com relação ao desfecho, 39% dos pacientes alcançaram remissão parcial ou completa. Albumina sérica inicial mais baixa e proteinúria de 24 horas inicial mais elevada foram fatores associados a pior prognóstico renal. Conclusões: De acordo com a nova classificação histológica, a grande maioria dos casos de GNMP foram classificados como sendo mediados por imunocomplexos. Houve poucas diferenças entre GNMP primária e secundária em relação às suas características clínicas e laboratoriais.

Membranoproliferative glomerulonephritis: current histopathological classification, clinical profile, and kidney outcomes.

INTRODUCTION: Membranoproliferative glomerulonephritis (MPGN) is a rare glomerular disease with a variable prognosis. A new classification based on the presence or absence of immunoglobulins and complement deposits in immunofluorescence microscopy (IF) of kidney biopsy has recently been proposed. The objectives of the study were to determine and compare the clinical, laboratory, and histopathological characteristics of those with primary or secondary MPGN, reclassify the primary ones based on IF findings, and evaluate kidney outcomes. METHODS: This was an observational retrospective cohort study carried out in a single center (UNIFESP), based on the data collected from medical records of patients followed from 1996 to 2019. RESULTS: Of 53 cases of MPGN, 36 (67.9%) were classified as primary and 17 (32.1%) as secondary MPGN. Most patients were hypertensive (84.9%) and had edema (88.7%) and anemia (84.9%); 33 (91.7%) patients classified as primary MPGN were reclassified as immune-complex-mediated and 3 (8.3%) as complement-mediated. The secondary MPGN group had hematuria more frequently (p <0.001) and a higher prevalence of deposits of IgG (p = 0.02) and C1q (p = 0.003). Regarding the outcome, 39% of the patients achieved partial or complete remission. Lower initial serum albumin and higher initial 24-hour proteinuria were factors associated with worst renal prognosis. CONCLUSIONS: According to the new histological classification, the vast majority of MPGN cases were classified as being mediated by immune complexes. There were few differences between primary and secondary MPGN in relation to their clinical and laboratory characteristics.

Development of an instrument to predict proliferative histological class in lupus nephritis based on clinical and laboratory data.

OBJECTIVES: To compare the correlations of histological class inferences based on clinical manifestations and laboratory tests between rheumatologists and nephrologists, to determine the associations of clinical and laboratory data with histological classes and to develop an instrument that can assist histological class identification in lupus nephritis (LN). METHODS: Retrospective study based on medical records of 80 systemic lupus erythematosus patients (SLICC criteria classification, 2012) who underwent kidney biopsy between 2010 and 2017. Two rheumatologists and two nephrologists received clinical and laboratory data and answered questions regarding which histological class was expected on kidney biopsy. Kappa (K) coefficient was used to assess agreement between evaluators. A decision tree was constructed using the chi-square interaction detector and logistic regression was performed for the development of the proliferative histological class predictor instrument. RESULTS: The mean age and disease duration were 33 ± 10.3 years and 11.5 ± 6.7 years, respectively. The level of agreement between the evaluators and kidney biopsy was poor (global K 0.364 ± 0.029; p < .001). Analyzing clinical and laboratory variables as predictors of proliferative histological class, patients with abnormal urinary sediment and positive anti-dsDNA antibodies presented 13.96 and 4.96 times higher risks of presenting class III or IV, respectively (p < 0.001). Our instrument has a sensitivity of 87.8% and specificity of 80%, using abnormal urinary sediment, anti-dsDNA antibodies, and serum creatinine as variables. CONCLUSIONS: Rheumatologists and nephrologists with experience in treating LN generated evaluations that correlated weakly with kidney biopsy. When kidney biopsy is unavailable or is contraindicated for medical reasons, instruments based on clinical and laboratory predictors may be helpful.

Recurrence of IgA Nephropathy after Kidney Transplantation in Adults.

BACKGROUND AND OBJECTIVES: In patients with kidney failure due to IgA nephropathy, IgA deposits can recur in a subsequent kidney transplant. The incidence, effect, and risk factors of IgA nephropathy recurrence is unclear, because most studies have been single center and sample sizes are relatively small. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a multicenter, international, retrospective study to determine the incidence, risk factors, and treatment response of recurrent IgA nephropathy after kidney transplantation. Data were collected from all consecutive patients with biopsy-proven IgA nephropathy transplanted between 2005 and 2015, across 16 "The Post-Transplant Glomerular Disease" study centers in Europe, North America, and South America. RESULTS: Out of 504 transplant recipients with IgA nephropathy, recurrent IgA deposits were identified by kidney biopsy in 82 patients; cumulative incidence of recurrence was 23% at 15 years (95% confidence interval, 14 to 34). Multivariable Cox regression revealed a higher risk for recurrence of IgA deposits in patients with a pre-emptive kidney transplant (hazard ratio, 3.45; 95% confidence interval, 1.31 to 9.17) and in patients with preformed donor-specific antibodies (hazard ratio, 2.59; 95% confidence interval, 1.09 to 6.19). After kidney transplantation, development of de novo donor-specific antibodies was associated with subsequent higher risk of recurrence of IgA nephropathy (hazard ratio, 6.65; 95% confidence interval, 3.33 to 13.27). Immunosuppressive regimen was not associated with recurrent IgA nephropathy in multivariable analysis, including steroid use. Graft loss was higher in patients with recurrence of IgA nephropathy compared with patients without (hazard ratio, 3.69; 95% confidence interval, 2.04 to 6.66), resulting in 32% (95% confidence interval, 50 to 82) graft loss at 8 years after diagnosis of recurrence. CONCLUSIONS: In our international cohort, cumulative risk of IgA nephropathy recurrence increased after transplant and was associated with a 3.7-fold greater risk of graft loss.

Effect of hearing aids on attention, memory, and auditory evoked potentials: A pragmatic, single-blinded, and randomised pilot clinical trial.

PURPOSE: To compare the effects of hearing aids and their technology levels (premium and basic) on attention, memory, brain response, and self-perceived benefit amongst individuals who were naïve to sound amplification. MATERIAL AND METHODS: A pragmatic, single-blinded, and randomised pilot clinical trial in three-parallel arms according to hearing aids technology: (a) premium; (b) basic; and (c) no amplification hearing devices. Participants were ≥60 years old with mild-to-moderate sensorineural symmetric hearing loss and naïve to sound amplification. We tested attention and memory skills, as well as brain response and self-perceived benefit before and after 12 weeks of using the hearing devices. The primary outcome was any improvement in the tests we performed. RESULTS: The participants who missed the follow-up (n = 2) were excluded from our final analysis. We ended up with 22 patients (A = 8, B = 6, and C = 8) who were 80.4 (±6.1) years old, predominantly female (63.63%), and poorly educated (3.8 ± 1.6 years). After the intervention, we observed differences in attention and memory scores (reverse counting, P < .01, 95% CI 2.2; 11.63; digit sequence repetition, P = .03, 95% CI -1.9; -0.05; delayed recall, P = .03, 95% CI -1.2; -0.05; recognition, P < .01, 95% CI -2.6; -0.45; and visual memory, P < .01, 95% CI -0.9; -0.15), but only reverse counting (A vs C, P < .01,95% CI 5.9; 20.55) and recognition (B vs C, P < .01, 95% CI -6.1; -0.88) were observed in pairwise comparisons. The difference in N1 wave latency (/g/ sound, P = .01,95% CI 2.1; 18.59) could not be confirmed in pairwise comparison. The self-perceived benefit questionnaire revealed no difference between groups A and B; the groups A and C differed in benefit (P < .01, 95% CI -2.2; -0.76), satisfaction (P = .02,95% CI -2.0;-0.21), residual participation restrictions (P = .01, 95% CI -2.9; -0.38), and quality of life (P = .03, 95% CI -1.4; -0.08); the groups B and C differed in benefit (P < .001, 95% CI -2.3; -0.96), and satisfaction (P = .01,95% CI -2.1; -0.29). CONCLUSION: In this study, premium and basic hearing aids impacted attention, memory, brain response, and self-perceived benefit similarly amongst individuals who were naïve to sound amplification after 12 weeks of using the hearing devices.

Autoantibodies against phospholipase A2 receptor in Brazilian patients with glomerular diseases.

BACKGROUND: Recently, great progress has been made in understanding the pathogenesis of membranous nephropathy (MN) with the discovery of autoantibodies (Abs) to M-type phospholipase A2 receptor (PLA2R) in serum and in immunocomplexes deposited in glomerulus in most adult patients with primary MN. OBJECTIVE: To evaluate the diagnostic performance of anti-PLA2R in Brazilian patients with MN, as well as to verify the possible association of anti-PLA2R serum levels with disease activity. METHODS: 117 patients with glomerular diseases confirmed by renal biopsy underwent routinely clinical and laboratory evaluation (serum creatinine and albumin, 24-h proteinuria, urinalysis, tests for etiological investigation) and determination of serum anti-PLA2R by ELISA. RESULTS: 67.5% of the patients had MN, 9.4% focal segmental glomerulosclerosis, 7.7% lupus nephritis class V and 15.4%, other proteinuric glomerular diseases. The mean level of glomerular filtration rate (estimated by the CKD-EPI formula) was 79.43 mL/min (12.00-151.20 mL/min), 24 h proteinuria of 2.89 g (0-14.90 g), serum albumin of 3.79 g/dL (1.20-4.80 g/dL). Anti-PLA2R was detected in 27 patients, all with active MN, being 26 primary and 1 secondary MN. Sensitivity and specificity rates for the test were 60.5-94.7%, and positive (PPV) and negative (NPV) predictive values were 92.9 and 67.9%, respectively. CONCLUSIONS: Anti-PLA2R showed high specificity and PPV for the diagnosis of primary MN in Brazilian patients. There was a strong correlation between disease activity and positive anti-PLA2R. This biomarker represents an important diagnostic tool for primary MN and may contribute to the monitoring of disease activity in such patients.

Cathepsin L in COVID-19: From Pharmacological Evidences to Genetics.

The coronavirus disease 2019 (COVID-19) pandemics is a challenge without precedent for the modern science. Acute Respiratory Discomfort Syndrome (ARDS) is the most common immunopathological event in SARS-CoV-2, SARS-CoV, and MERS-CoV infections. Fast lung deterioration results of cytokine storm determined by a robust immunological response leading to ARDS and multiple organ failure. Here, we show cysteine protease Cathepsin L (CatL) involvement with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19 from different points of view. CatL is a lysosomal enzyme that participates in numerous physiological processes, including apoptosis, antigen processing, and extracellular matrix remodeling. CatL is implicated in pathological conditions like invasion and metastasis of tumors, inflammatory status, atherosclerosis, renal disease, diabetes, bone diseases, viral infection, and other diseases. CatL expression is up-regulated during chronic inflammation and is involved in degrading extracellular matrix, an important process for SARS-CoV-2 to enter host cells. In addition, CatL is probably involved in processing SARS-CoV-2 spike protein. As its inhibition is detrimental to SARS-CoV-2 infection and possibly exit from cells during late stages of infection, CatL could have been considered a valuable therapeutic target. Therefore, we describe here some drugs already in the market with potential CatL inhibiting capacity that could be used to treat COVID-19 patients. In addition, we discuss the possible role of host genetics in the etiology and spreading of the disease.

Familial Focal Segmental Glomerulosclerosis With Late-Onset Presentation and R229Q/R291W Podocin Mutations.

INTRODUCTION: Pathogenic variants in different genes have been described as involved in the development of familial focal segmental glomerulosclerosis (FSGS). A more precise genotype-phenotype correlation would be helpful to better characterize the clinical and laboratorial manifestations of this disease, as well as response to treatment. We analyzed podocin (NPHS2) gene variants in 50 members of four generations of a family with late-onset presentation of glomerular disease. RESULTS AND DISCUSSION: The NPHS2 gene variants R229Q and/or R291W were detected in several individuals, and the phenotype of FSGS with progressive loss of renal function was observed in all the family members carrying both mutations simultaneously. Patients manifested ongoing proteinuria over the years and progressive loss of renal function, which in three women culminated in renal replacement therapy by the 4th decade of life. In two affected patients with nephrotic syndrome, remission was not reached by the use of corticosteroids and other immunosuppressive drugs. The R229Q variant was pathogenic only when trans-associated with specific mutations, as the R291W variant in this family. CONCLUSION: Coexistence of the two NPHS2 variants R229Q and R291W in compound heterozygosis was a determinant of the FSGS phenotype. The presence of these variants alone in heterozygosis did not cause significant proteinuria.

Pre-exposure prophylaxis during the SARS-CoV-2 pandemic: can PrEP prevent COVID-19-related symptoms?

It has been speculated that some drugs can be used against SARS-CoV-2. As for antiretrovirals, the follow-up of pre-exposure prophylaxis (PrEP) users during the coronavirus disease 2019 (COVID-19) outbreak may help to understand the potential protective effect of PrEP against SARS-CoV-2. We aimed to identify associations between oral PrEP use and COVID-19-related symptoms self-reporting. Phone call interviews or digital investigation (through WhatsApp® or e-mail) about oral PrEP regular use, social distancing, exposure to suspected or confirmed cases of SARS-CoV-2 infection and COVID-19-related symptoms. Among 108 individuals, the majority were cisgender, white and gay men. Although most of the individuals engaged in social distancing (68.52%), they kept on taking PrEP (75.93%). Few people have had contact with suspected or confirmed cases of COVID-19 (12.04%), but some had COVID-19-related symptoms the month before the interview (27.78%) including rhinorrheoa (56.67%), cough (53.33%), asthaenia (50.00%) and headache (43.33%). Also, oral PrEP was associated with lower self-reporting COVID-19-symptoms (OR 0.26, 95% CI 0.07-0.96, P = 0.04; h = 0.92) even after controlling confounders as social distancing, age, body-mass index and morbidities . In our sample, the regular use of oral PrEP was associated with lower self-reporting of COVID-19-related symptoms during the outbreak in São Paulo, Brazil.

Corrigendum: Autoantibodies in renal diseases - clinical significance and recent developments in serological detection.

[This corrects the article on p. 221 in vol. 6, PMID: 26029207.].

Correlation between GLA variants and alpha-Galactosidase A profile in dried blood spot: an observational study in Brazilian patients.

BACKGROUND: Fabry disease is a rare X-linked inherited disorder caused by deficiency of α-Galactosidase A. Hundreds of mutations and non-coding haplotypes in the GLA gene have been described; however, many are variants of unknown significance, prompting doubts about the diagnosis and treatment. The α-Galactosidase A enzymatic activity in dried blood spot (DBS) samples are widely used for screening purposes; however, even when values below the normal are found, new tests are required to confirm the diagnosis. Here we describe an analysis of GLA variants and their correlation with DBS α-Galactosidase A enzymatic activity in a large Brazilian population with Fabry disease symptoms. RESULTS: We analyzed GLA variants by DNA sequencing of 803 male patients with suspected Fabry disease or belonging to high-risk populations; in 179 individuals, 58 different exonic variants were detected. From these, 50 are variants described as pathogenic and eight described as variants of unknown significance. The other individuals presented complex non-coding haplotypes or had no variants. Interestingly, the enzymatic activity in DBS was different among pathogenic variants and the other genotypes, including variants of unknown significance; the first presented mean of 12% of residual activity, while the others presented levels above 70% of the activity found in healthy controls. CONCLUSION: The activity of α-Galactosidase A in DBS was markedly reduced in males with known pathogenic variants when compared with subjects presenting variants of unknown significance, non-coding haplotypes, or without variants, indicating a possible non-pathogenic potential of these latter genotypes. These findings bring a better understanding about the biochemical results of α-Galactosidase A in DBS samples, as well as the possible non-pathogenic potential of non-coding haplotypes and variants of unknown significance in GLA gene. These results certainly will help clinicians to decide about the treatment of patients carrying variants in the gene causing this rare but life-threatening disease.

Functional Characterization and Pharmacological Evaluation of a Novel GLA Missense Mutation Found in a Severely Affected Fabry Disease Family.

BACKGROUND: Fabry disease (FD) is a rare X-linked storage disorder resulting from the deficient activity of the lysosomal hydrolase α-galactosidase A (α-Gal A). Here we describe a 23-year-old man with FD possessing a novel mutation in the GLA gene, the evaluation of his family, and the functional characterization of the novel variant. METHODS: Two generations of a family were screened for FD by clinical symptoms and low enzymatic activity. This step was followed by DNA sequencing that showed a novel GLA missense mutation. To confirm the pathogenicity potential of the mutation, we employed site-directed polymerase chain reaction mutagenesis. GLA wild-type and mutant plasmids were transfected into mammalian cells; RNA and proteins were extracted for expression and analysis of enzymatic activity. RESULTS: The patient presents the variant p.Asn34Asp in the GLA and had several manifestations of FD since adolescence. The investigation of the deficiency of α-Gal A was initiated due to stage 4 of chronic kidney disease. All family members carrying the novel mutation presented early symptoms, including index case's mother, who received a renal transplant when she was 35 years old. In silico and in vitro analysis confirmed the pathogenic potential of the mutation p.Asn34Asp showing that the enzyme had only 4% of residual activity due to protein misfolding. The ability of the pharmacological chaperone 1-deoxygalactonojirimycin to recover the mutant was confirmed, producing 37.5% of residual activity. CONCLUSION: In this work, we present a novel missense mutation in GLA that leads to the production of a catalytically competent α-Gal A, which is degraded before its delivery to the lysosome, promoting severe manifestations of FD, with a very similar disease course in affected men and women.

Clinical Presentation, Outcomes, and Treatment of Membranous Nephropathy after Transplantation.

There are scarce data about clinical presentation and outcomes of posttransplant membranous nephropathy (MN), and few reports include a large number of patients. This was a retrospective cohort including adult patients with posttransplant MN transplanted between 1983 and 2015 in a single center (n=41). Only patients with histological diagnosis of MN in kidney grafts were included. Clinical and laboratory presentation, histological findings, treatment, and outcomes were detailed. Patients were predominantly male (58.5%), with a mean age of 49.4 ± 13.2 years; 15 were considered as recurrent primary MN; 3 were class V lupus nephritis; 14 were considered as de novo cases, 7 secondary and 7 primary MN; and 9 cases were considered primary but it was not possible to distinguish between de novo MN and recurrence. Main clinical presentations were proteinuria (75.6%) and graft dysfunction (34.1%). Most patients with primary recurrent and de novo primary MN were submitted to changes in maintenance immunosuppressive regimen, but no standard strategy was identified; 31 patients presented partial or complete remission, and glomerulopathy appeared not to impact graft and patient survival.

Clinical Features, Treatment and Prognostic Factors of Post-Transplant Immunoglobulin A Nephropathy.

BACKGROUND Initially described as a relatively benign condition, recent studies report graft loss in up to 50% of the patients with post-transplant IgA nephropathy. There is no evidence for the best therapeutic approach, and prognostic factors remain to be elucidated. MATERIAL AND METHODS Single center retrospective analysis of patients >12 years old, with clinically relevant post-transplant IgA nephropathy (proteinuria ≥1.0 g/g and/or graft dysfunction) and ≥6 months follow-up after diagnosis (n=47). RESULTS Living donor transplants represented 85% of cases. Dysmorphic hematuria (100%), blood pressure elevation (95.7%), renal dysfunction (70.2%) and subnephrotic proteinuria (60.6%) predominated at presentation. Using the Oxford Classification, mesangial proliferation was the main histological lesion (91%). Treatment consisted mostly of blockade of the renin angiotensin system (89.4%) and modification of immunosuppression (85.1%), mainly by increasing oral steroids dose (83%), with venous pulse therapy in 63.8% of cases. Partial and complete remission occurred in 48.9% and 17% of cases, respectively. One patient died (sepsis) and 15 patients (31.9%) lost their grafts due to nephropathy. The percentage of decrease in glomerular filtration rate at diagnosis was independently associated with partial remission (HR 0.97, 95% CI 0.94-0.99, p=0.01) and graft loss (HR 1.13, 95% CI 1.06-1.20, p<0.001). Deceased donor (HR 28.04, 95% CI 4.41-178.39, p<0.001) and donor age (HR 1.1, 95% CI 1.04-1.16, p=0.001) were also risk factors for graft loss. CONCLUSIONS Despite treatment, most patients with post-transplant IgA nephropathy in this cohort study presented unfavorable outcomes, and graft dysfunction at diagnosis appeared to be the main prognostic marker.

Pregnancy as an early stress test for cardiovascular and kidney disease diagnosis.

OBJECTIVES: Pregnancy is a cardiometabolic and renal stress test for women, primarily when associated with hypertension syndrome, which can have deleterious effects in the long term. We undertook this study to make a long-term evaluation on these women. STUDY DESIGN: A retrospective cohort study was conducted to investigate voluntary women who had pregnancy-induced hypertension syndrome versus normal pregnancy. MAIN OUTCOME MEASURES: We evaluated a total of 85 women, divided in case (n = 25) and control (n = 60) groups, by clinical, anthropometric and epidemiological profiles, general, metabolic and renal tests, and risk stratification for cardiovascular disease (CVD) and chronic kidney disease (CKD). RESULTS: The case group showed a higher incidence of hypertension (P = .003), shorter period between its diagnosis and end of pregnancy (P < .001) and lower age at diagnosis (P = .033); higher weight (P < .001), body mass index (BMI) (P < .001), waist-to-height ratio (p = .001) and abdominal circumference (P < .001); higher fat percentage (P = .004) and weight to lose (P < .001) as measured by bioimpedance; lower estimate glomerular filtration rate (eGFR) by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (P = .021), greater difference between estimated vascular age and real age (P = .008) according to Framingham Risk Score (2008) and higher frequency of metabolic syndrome (P < .001). CONCLUSIONS: Women who had pregnancy-induced hypertension syndrome were found with a higher incidence of obesity, metabolic syndrome and hypertension, earlier onset of hypertension, higher estimated vascular age and lower eGFR. These findings reinforce the importance of investigating the history of hypertension syndrome in pregnancy, which should be considered an indicator to be followed long term after childbirth.