Podocytopathies associated with familial partial lipodystrophy due to LMNA variants: report of two cases.

Lipodystrophies are characterized by complete or selective loss of adipose tissue and can be acquired or inherited. Familial partial lipodystrophy (FPLD) is a hereditary lipodystrophy commonly caused by mutations in the LMNA gene. Herein, we report two cases of FPLD associated with podocytopathies. Patient 1 was diagnosed with FPLD associated with the heterozygous p.Arg482Trp variant in LMNA and had normal glucose tolerance and hyperinsulinemia. During follow-up, she developed nephroticrange proteinuria. Renal biopsy was consistent with minimal change disease. Patient 2 was diagnosed with FPLD associated with a de novo heterozygous p.Arg349Trp variant in LMNA. Microalbuminuria progressed to macroalbuminuria within 6 years and tonephrotic range proteinuria in the last year. He remained without diabetes and with hyperinsulinemia. Renal biopsy revealed focal segmental glomerulosclerosis not otherwise specified. This report provides further evidence of variable features of lipodystrophy associated with LMNA variants and the importance of long-term follow-up with evaluation of kidney dysfunction.

Urinary CD80 and Serum suPAR as Biomarkers of Glomerular Disease among Adults in Brazil.

INTRODUCTION: Urinary CD80 has been shown to have good specificity for minimal change disease (MCD) in children. However, the investigation of circulating factors such as soluble urokinase plasminogen activator receptor (suPAR) as biomarkers of focal segmental glomerulosclerosis (FSGS) is quite controversial. The objective of this study was to determine whether urinary CD80 and serum suPAR can be used for the diagnosis of MCD and FSGS, respectively, in the adult population of Brazil. We also attempted to determine whether those biomarkers assess the response to immunosuppressive treatment. METHODS: This was a prospective study in which urine and blood samples were collected for analysis of CD80 and suPAR, respectively, only in the moment of renal biopsy, from patients undergoing to diagnostic renal biopsy. At and six months after biopsy, we analyzed serum creatinine, serum albumin, and proteinuria in order to evaluate the use of the CD80 and suPAR collected in diagnosis as markers of response to immunosuppressive treatment. In healthy controls were collected urinary CD80 and proteinuria, serum suPAR, and creatinine. RESULTS: The results of 70 renal biopsies were grouped, by diagnosis, as follows: FSGS (n = 18); membranous nephropathy (n = 14); MCD (n = 5); and other glomerulopathies (n = 33). There was no significant difference among the groups in terms of the urinary CD80 levels, and serum suPAR was not significantly higher in the FSGS group, as would have been expected. Urinary CD80 correlated positively with nephrotic syndrome, regardless of the type of glomerular disease. Neither biomarker correlated with proteinuria at six months after biopsy. CONCLUSION: In adults, urinary CD80 can serve as a marker of nephrotic syndrome but is not specific for MCD, whereas serum suPAR does not appear to be useful as a diagnostic or treatment response marker.

Systemic amyloidosis journey from diagnosis to outcomes: a twelve-year real-world experience of a single center in a middle-income country.

BACKGROUND: Systemic amyloidosis is caused by the deposition of misfolded protein aggregates in tissues, leading to progressive organ dysfunction and death. Epidemiological studies originate predominantly from high-income countries, with few data from Latin America. Due to the non-specific clinical manifestations, diagnosing amyloidosis is often challenging and patients experience a long journey and delay in diagnosis. This study aimed to assess clinical and laboratory characteristics, the diagnostic journey, and outcomes of patients with biopsy-proven systemic amyloidosis diagnosed between 2009 and 2020 at a university referral center in a middle-income Latin American country. Patients´ medical records were retrospectively reviewed. RESULTS: One hundred and forty-three patients were included. The median age at diagnosis was 60 years and 54% were male. Until the diagnosis, most of the patients (52%) were seen by at least 3 specialists, the main ones being: general practitioners (57%), nephrologists (45%), and cardiologists (38%). The most common manifestations were renal (54%) and cardiac (41%) disorders, and cachexia was seen in 36% of patients. In 72% of the cases, ≥ 2 biopsies were required until the final diagnosis. The median time from symptoms onset to diagnosis was 10.9 months, and most patients (75%) had ≥ 2 organs involved. The following subtypes were identified: AL (68%), ATTR (13%), AA (8%), AFib (4%), and inconclusive (7%). Median OS was 74.3 months in the non-AL subgroup and 18.5 months in AL. Among AL patients, those with advanced cardiac stage had the worst outcome [median OS 8.6 months versus 52.3 for stage III versus I-II, respectively (p < 0.001)]. AL subtype, cardiac involvement, and ECOG ≥ 2 were identified as independent risk factors for reduced survival. CONCLUSIONS: Systemic amyloidosis is still an underdiagnosed condition and the delay in its recognition leads to poor outcomes. Medical education, better diagnostic tools, improvement in access to therapies, and establishment of referral centers may improve patient outcomes in middle-income countries.

Diagnosis and Course of Membranous Nephropathy in Adults: Comparison by Age Group.

INTRODUCTION: There have been few studies comparing younger and older adults with membranous nephropathy. The objective of this study was to compare younger and older patients with membranous nephropathy, in terms of the clinical, etiological, remission, and survival data. METHOD: This was a retrospective study of patients with membranous nephropathy who underwent renal biopsy between 2009 and 2017. RESULTS: We included 214 patients with membranous nephropathy. At diagnosis, 169 (79%) of those patients were <60 years of age and 45 (21%) were ≥60 years of age. There was a predominance of males in both groups. The degree of proteinuria and the prevalence of hematuria did not differ significantly between the groups. However, the median serum creatinine level was higher in the ≥60-year group as was the prevalence of hypertension. Of the patients evaluated, 36 (16.8%) had secondary membranous nephropathy. Although the proportions of infectious and autoimmune causes were comparable between the two groups, neoplastic etiologies were more common in the ≥60-year group. A total of 86 in the <60-year group and 25 in the ≥60-year group were followed long term, and partial or complete remission was achieved in 68.5% and 68.0% of the younger and older patients, respectively. However, whom progressed to requiring dialysis eight (9.3%) were in the <60-year group patients and eight (32.0%) of the ≥60-year group patients (p = 0.0045). CONCLUSION: Despite having worse renal function at diagnosis, older patients with membranous nephropathy appear to have remission rates comparable to those of younger patients with the disease, which demonstrates the benefits of seeking diagnosis and treatment.

IgA nephropathy in patients with serum anti-neutrophil cytoplasmic autoantibody (ANCA) positivity: case series / Nefropatia por IgA em pacientes com anticorpo anticitoplasma de neutrófilo positivo: série de casos

Abstract Some cases of patients with IgA nephropathy diagnosed via kidney biopsy and antineutrophil cytoplasmic antibody (ANCA) positivity have been reported. This article describes a case series comprising patients with IgA nephropathy and ANCA positivity seen at a medical center in the city of São Paulo, Brazil, from 1996 to 2016. A total of 111 patients underwent diagnostic kidney biopsies for IgA nephropathy. Five were ANCA-positive at the time of diagnosis; their mean age was 45 ± 15.3 years and they were predominantly females with a mean proteinuria of 2.2 ± 0.9 g/day and a median serum creatinine level of 2.5 (2.0 - 8,6) mg/dL; all had hematuria. Four of the five were cANCA-positive (80%); all had normal serum C3 and C4 levels; and 80% were positive for ANA. One case presented an association with infection, but no associations were found with medication. One patient had granuloma and another had a collapsing lesion. This article describes the cases of five ANCA-positive patients (with predominantly cANCA positivity) submitted to diagnostic kidney biopsies for IgA nephropathy; one patient had a collapsing lesion, but progressed well.

Resumo Alguns casos clínicos de biópsia renal diagnóstica de nefropatia por IgA em pacientes com títulos séricos positivos de anticorpo anticitoplasma de neutrófilos (ANCA) vêm sendo publicados. Descreve-se uma série de casos de nefropatia por IgA com ANCA positivo de centro único da cidade de São Paulo, Brasil, no período de 1996 a 2016. No período estudado, houve 111 pacientes com biópsia renal com diagnóstico de nefropatia por IgA; destes, 5 tinham ANCA positivo ao diagnóstico com média de idade de 45 ± 15,3 anos, predominando o sexo feminino, com média de proteinúria de 2,2 ± 0,9 g/dia, hematúria presente em 100% dos casos e mediana de creatinina sérica de 2,5 (2,0 - 8,6) mg/dL. O cANCA foi o padrão mais encontrado, em 4 dos 5 casos (80%), com os níveis séricos das frações de complemento C3 e C4 normais em todos e FAN positivo em 80% dos casos. Houve associação com infecções em um caso, mas sem associação com medicações. À microscopia óptica, um dos pacientes tinha granuloma e outro, lesão colapsante. Em resumo, descreve-se cinco casos de pacientes com biopsia renal diagnóstica de nefropatia por IgA com ANCA sérico positivo predominando cANCA, destacando um paciente desse grupo com microscopia óptica com lesão colapsante que, apesar disso, teve boa evolução.

IgA nephropathy in patients with serum anti-neutrophil cytoplasmic autoantibody (ANCA) positivity: case series.

Some cases of patients with IgA nephropathy diagnosed via kidney biopsy and antineutrophil cytoplasmic antibody (ANCA) positivity have been reported. This article describes a case series comprising patients with IgA nephropathy and ANCA positivity seen at a medical center in the city of São Paulo, Brazil, from 1996 to 2016. A total of 111 patients underwent diagnostic kidney biopsies for IgA nephropathy. Five were ANCA-positive at the time of diagnosis; their mean age was 45 ± 15.3 years and they were predominantly females with a mean proteinuria of 2.2 ± 0.9 g/day and a median serum creatinine level of 2.5 (2.0 - 8,6) mg/dL; all had hematuria. Four of the five were cANCA-positive (80%); all had normal serum C3 and C4 levels; and 80% were positive for ANA. One case presented an association with infection, but no associations were found with medication. One patient had granuloma and another had a collapsing lesion. This article describes the cases of five ANCA-positive patients (with predominantly cANCA positivity) submitted to diagnostic kidney biopsies for IgA nephropathy; one patient had a collapsing lesion, but progressed well.

Methimazole-Induced ANCA Vasculitis: A Case Report.

Rapidly progressive glomerulonephritis (RPGN) is a syndrome which presents rapid loss of renal function. Vasculitis represents one of the major causes, often related to anti-neutrophil cytoplasmic antibodies (ANCA). Herein, we report a case of methimazole-induced ANCA-associated vasculitis. A 35-year-old woman complained of weight loss and fatigue for 2 weeks and attended the emergency room with alveolar hemorrhage. She had been diagnosed with Graves' disease and had been taking methimazole in the past 6 months. Her physical examination showed pulmonary wheezing, hypertension and signs of respiratory failure. Laboratory tests revealed urea 72 mg/dL, creatinine 2.65 mg/dL (eGFR CKD-EPI: 20 mL/min/1.73 m2), urine analysis with >100 red blood cells per high-power field, 24 h-proteinuria: 1.3 g, hemoglobin 6.6 g/dL, white-cell count 7700/mm3, platelets 238,000/mm3, complement within the normal range, negative viral serological tests and ANCA positive 1:80 myeloperoxidase pattern. Chest tomography showed bilateral and diffuse ground-glass opacities, and bronchial washing confirming alveolar hemorrhage. A renal biopsy using light microscopy identified 27 glomeruli (11 with cellular crescentic lesions), focal disruption in glomerular basement membrane and fibrinoid necrosis areas, tubulitis and mild interstitial fibrosis. Immunofluorescence microscopy showed IgG +2/+3, C3 +3/+3 and Fibrinogen +3/+3 in fibrinoid necrosis sites. She was subsequently diagnosed with crescentic pauci-immune glomerulonephritis, mixed class, in the setting of a methimazole-induced ANCA vasculitis. The patient was treated with methimazole withdrawal and immunosuppressed with steroids and cyclophosphamide. Four years after the initial diagnosis, she is currently being treated with azathioprine, and her exams show creatinine 1.30 mg/dL (eGFR CKD-EPI: 52 mL/min/1.73 m2) and negative p-ANCA.

Renal thrombotic microangiopathy associated to worse renal prognosis in Lupus Nephritis.

INTRODUCTION: Renal thrombotic microangiopathy (rTMA) is one of many vascular findings in Lupus Nephritis (LN). However, the influence of rTMA on prognosis has not been well established. The objective of this study was to evaluate the clinical and pathological aspects of patients with lupus and rTMA in kidney biopsy. METHODS: Analysis of medical reports and kidney biopsy of 253 patients with LN, between January 2012 and December 2018. RESULTS: Among our 253 patients, 43 (17%) showed acute or chronic TMA lesions on kidney histology This group had a significantly lower estimated glomerular filtration rate (eGFR) at the time of biopsy (24.1 vs. 64.15 ml/min/1.73m2, p < 0.001), at 1 year of follow up (28.1 vs. 90.7 ml/min/1.73m2, p < 0.001), and at the end of follow up (25.4 vs. 81.55 ml/min/1.73m2, p < 0.001). More patients in the rTMA group reached the composite endpoint of eGFR < 15 mL/min/1.73m2 or death or dialysis (82.9% vs. 32.9%, p < 0.001). When comparing the classical clinical TMA features, the rTMA group had higher percentages of anemia, thrombocytopenia, low haptoglobin levels, but not higher lactate dehydrogenase (LDH) levels (> 214 U/L). Combining these variables in a definition of clinical TMA, the rTMA group had a statistically higher percentage of clinical TMA (20.9% vs. 4.33%, p = 0.001). As expected, TMA group showed higher systolic blood pressure (SBP) (130 vs 129.5 mmHg, p = 0.01). Concerning histopathological features, rTMA group had significantly higher activity (9.0 vs. 6.0, p = 0.001) and chronicity (4.0 vs. 3.0, p = 0.001) scores, also a higher percentage of patients presented with crescents (76.7% vs. 57.1%, p = 0.012). CONCLUSIONS: The classical clinical TMA criteria were unable to predict the presence of tissue TMA, suggesting a probably renal-limited TMA that may occur independently of systemic evident factors. Therefore, renal biopsy remains the critical method for diagnosing an important prognostic feature.

Renal Outcomes in Brazilian Patients with Immunoglobulin A Nephropathy and Cellular Crescentic Lesions.

BACKGROUND AND AIM: Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulopathy. The Oxford classification was recently updated to include crescents as markers of poor prognosis. The aim of this study was to evaluate the impact of cellular crescents on the prognosis of patients with IgAN in Brazil. METHODS: This was a single-centre retrospective analysis of medical records and renal biopsies in patients with IgAN. The renal biopsy findings were classified according to the revised Oxford classification: mesangial hypercellularity, endocapillary hypercellularity (E), segmental glomerulosclerosis (S), tubular atrophy or interstitial fibrosis (T), and crescent formation (C). We evaluated a composite outcome (progression to end-stage renal disease or creatinine doubling). We performed analyses between the patients with crescents in the renal biopsy specimen (C1/C2 group) and those without such crescents (C0 group). RESULTS: We evaluated 111 patients, of whom 72 (65.0%) were women, 80 (72.0%) self-identified as White, 73 (65.6%) were hypertensive, and 95 (85.6%) had haematuria. The distribution of patients according to cellular crescentic lesions was: C0, 80 (72%); C1, 27 (24.4%); C2, 4 (3.6%). The composite outcome was observed in 33 (29.72%) of the 111 patients. In comparison with the C0 group, the C1/C2 group had higher proportions of patients with hypertension (p = 0.04), haematuria (p = 0.03), worse serum creatinine (p = 0.0007), and worse estimated glomerular filtration rate (p = 0.0007). The C1/C2 group also had higher proportions of patients in whom the biopsy specimen was classified as E1 (p = 0.009), S1 (p = 0.001), or T1/T2 (p = 0.03), In addition, the mean follow-up period was shorter in the C1/C2 group (p < 0.0001). Furthermore, the composite outcome was observed in a greater proportion of patients and in a shorter length of time in the C1/C2 group than in the C0 group (p = 0.002 and p = 0.0014, respectively). In a Cox regression analysis, the independent risk factors for the composite outcome had Oxford classifications of S1, T1/T2, and C1/C2. CONCLUSION: Oxford classification findings of S1, T1/T2, or C1/C2 were independent risk factors for the composite outcome, corroborating previous studies.

Schistosomiasis-associated glomerulopathy: Clinical aspects, pathological characteristics, and renal outcomes
.

BACKGROUND: In Brazil, schistosomiasis is caused only by Schistosoma mansoni, occurring in the northeastern and southeastern regions. Schistosomiasis primarily affects the liver and gastrointestinal tract, although the kidneys can also be affected, mainly in the form of glomerulopathies. Here, we describe the characteristics of patients with schistosomiasis-associated glomerulopathies, including treatment and renal outcomes. MATERIALS AND METHODS: This was a retrospective analysis of patients diagnosed with schistosomiasis-associated glomerulopathy between 2002 and 2017. Clinical, biochemical, and histopathological (kidney biopsy) data were evaluated. RESULTS: Of the 24 patients evaluated, 19 (79.1%) were male and 16 (66.4%) were White. The mean age was 38.58 ± 9.83 years. We observed the hepatosplenic form of schistosomiasis in 15 patients (68.1%), nephrotic-nephritic syndrome in 13 (54.1%), hematuria in 20 (83.3%), and hypertension in 18 (75.0%). Renal histology showed a predominance of membranoproliferative pattern (n = 17/70.8%). On immunofluorescence, 19 patients (82.6%) showed immunoglobulin M (IgM) expression, 10 (43.4%) showed IgM+IgG expression, and 1 (4.3%) showed a "full house" pattern. The median follow-up time was 59.70 months, by the end of which 9 patients (37.5%) had developed end-stage renal disease (ESRD). Baseline serum creatinine was higher among the patients who developed ESRD than among those who did not (1.99 ± 1.08 vs. 1.34 ± 0.46 mg/dL, p = 0.05). CONCLUSION: Our study is one of the rare clinical studies on schistosomiasis-associated glomerulopathy with a long follow-up and renal endpoints, showing that one third of our patients, independent of their histological form, progress to dialysis.
.

Atypical presentation of acute post-infectious glomerulonephritis in patients with sickle cell disease: report of two cases.

BACKGROUND: Sickle cell disease (SCD) is a highly prevalent genetic disease worldwide. In the natural evolution of SCD, glomerular lesions can develop, presenting histopathological patterns of segmental or focal membranoproliferative glomerulosclerosis, with or without thrombotic microangiopathy. We report two cases of acute post-infectious glomerulonephritis (APIGN), with atypical presentations, in patients with SCD. CASE PRESENTATION: Case 1: An 18-year-old female with SCD presented with a 21-day history of progressive oedema, accompanied by dyspnoea, productive cough, fever, and chest pain. Blood tests showed the following: haemoglobin 6.1 g/dl; leucocytes 18,820 cells/mm3; and creatinine 0.49 mg/dl. A urine sample evidenced leucocyturia and haematuria. The 24-h proteinuria was 8.99 g, serum albumin level was 1.2 g/dl, low serum C3 levels and high levels of anti-streptolysin O. Renal biopsy was consistent with APIGN. The patient was treated with diuretic and anti-proteinuric agents, subsequently evolving to reversal of the renal alterations. Case 2: A 12-year-old male with SCD presented with a 20-day history of a non-productive cough and progressive oedema, together with hypertension. The serum creatinine concentration was 0.48 mg/dl. A urine sample evidenced leukocyturia and haematuria. The 24-h proteinuria was 12.5 g, and the serum albumin level was 2.6 g/dl. The levels of C3 and C4 were normal. Renal biopsy revealed APIGN. The patient was treated with diuretic and anti-proteinuric agents, subsequently evolving reversal of the renal alterations. CONCLUSIONS: The presentation of the two cases reported here are not typical of SCD-related kidney injury. Analysis of the renal biopsy specimens elucidated the diagnosis, affecting the prognosis, because that of APIGN is highly favourable, unlike that of nephrotic syndrome associated with SCD glomerulopathy.

Chronic nicotine exposure reduces klotho expression and triggers different renal and hemodynamic responses in klotho-haploinsufficient mice.

The klotho gene, which encodes a single-pass transmembrane protein and a secreted protein, is expressed predominantly by the distal renal tubules and is related to calcium phosphorus metabolism, ion channel regulation, intracellular signaling pathways, and longevity. Klotho deficiency aggravates acute kidney injury and renal fibrosis. Exposure to nicotine also worsens kidney injury. Here, we investigated renal Klotho protein expression in a mouse model of chronic (28-day) nicotine exposure, in which mice received nicotine or vehicle (saccharine) in drinking water, comparing wild-type (WT) mice, klotho-haploinsufficient ( kl/+) mice, and their respective controls, in terms of the effects of that exposure. Nicotine exposure was associated with a significant decline in renal Klotho expression in WT and kl/+ mice as well as a reduction in the glomerular filtration rate in WT mice. Although plasma electrolytes were similar among the groups, fractional excretion of sodium was reduced in both nicotine-exposed groups. The nicotine-WT mice presented augmented baroreflex sensitivity to nitroprusside and augmented sympathetic cardiac modulation. However, nicotine- kl/+ mice presented higher plasma levels of urea and aldosterone together with a higher α-index (spontaneous baroreflex) and higher peripheral sympathetic modulation, as evaluated by spectral analysis. We can conclude that nicotine downregulates Klotho expression as well as that renal and autonomic responses to nicotine exposure are modified in kl/+ mice.