RESUMEN
Glomerulomegaly and focal segmental glomerulosclerosis are histopathological hallmarks of obesity-related glomerulopathy (ORG). Podocyte injury and subsequent depletion are regarded as key processes in the development of these glomerular lesions in patients with ORG, but their impact on long-term kidney outcome is undetermined. Here, we correlated clinicopathological findings and podocyte depletion retrospectively in patients with ORG. Relative (podocyte density) and absolute (podocyte number per glomerulus) measures of podocyte depletion were estimated using model-based stereology in 46 patients with ORG. The combined endpoint of kidney outcomes was defined as a 30% decline in estimated glomerular filtration rate (eGFR) or kidney failure. Patients with lower podocyte density were predominantly male and had larger body surface area, greater proteinuria, fewer non-sclerotic glomeruli, larger glomeruli and higher single-nephron eGFR. During a median follow-up of 4.1 years, 18 (39%) patients reached endpoint. Kidney survival in patients with lower podocyte density was significantly worse than in patients with higher podocyte density. However, there was no difference in kidney survival between patient groups based on podocyte number per glomerulus. Cox hazard analysis showed that podocyte density, but not podocyte number per glomerulus, was associated with the kidney outcomes after adjustment for clinicopathological confounders. Thus, our study demonstrates that a relative depletion of podocytes better predicts long-term kidney outcomes than does absolute depletion of podocytes. Hence, the findings implicate mismatch between glomerular enlargement and podocyte number as a crucial determinant of disease progression in ORG.
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Tasa de Filtración Glomerular , Obesidad , Podocitos , Humanos , Podocitos/patología , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Obesidad/complicaciones , Adulto , Glomeruloesclerosis Focal y Segmentaria/patología , Glomeruloesclerosis Focal y Segmentaria/etiología , Glomeruloesclerosis Focal y Segmentaria/complicaciones , Glomérulos Renales/patología , Progresión de la Enfermedad , Proteinuria/etiología , Proteinuria/patología , Recuento de Células , Factores de Tiempo , Pronóstico , Modelos de Riesgos ProporcionalesRESUMEN
BACKGROUND: The association between proteinuria, which is also an indicator of chronic kidney disease (CKD), and coronavirus disease 2019 (COVID-19) severity is unclear. METHODS: We selected 342 hospitalized patients with COVID-19 diagnosed via polymerase chain reaction testing between February 2020 and October 2022 and who had at least one urinalysis 14-365 days before admission. RESULTS: Proteinuria before admission was associated neither with oxygen administration nor developing pneumonia in multivariate analysis (odds ratio [OR] 1.03; 95% confidence interval (CI) 0.44-2.40, p = 0.95 and OR 1.01; 95% CI 0.47-2.17, p = 0.98, respectively). Proteinuria on admission was associated both with oxygen administration and developing pneumonia in multivariate analysis (OR 3.29; 95% CI 1.37-7.88, p < 0.01 and OR 3.81; 95% CI 1.68-8.62, p < 0.01, respectively). The percentage of patients with proteinuria on admission was significantly higher than those before admission (37.4% vs. 17.8%; p < 0.01). In the subgroup analysis, proteinuria on admission among patients with eGFR ≥ 60 mL/min/1.73 m2 was associated with both oxygen administration and developing pneumonia (OR 4.86; 95% CI 1.22-19.38, p = 0.03, OR 3.65; 95% CI 1.06-12.58, p = 0.04, respectively). In contrast, proteinuria on admission among patients with eGFR < 60 mL/min/1.73 m2 was associated with developing pneumonia (OR 6.45; 95%CI 1.78-23.35, p = 0.01), not with oxygen administration (OR 3.28; 95% CI 0.92-11.72, p = 0.07). CONCLUSIONS: Although underlying proteinuria before admission was not associated with COVID-19 severity, proteinuria on admission was associated with oxygen demand and developing pneumonia.
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COVID-19 , Neumonía , Insuficiencia Renal Crónica , Humanos , COVID-19/complicaciones , Proteinuria/complicaciones , Neumonía/complicaciones , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/epidemiología , Oxígeno , Factores de RiesgoRESUMEN
BACKGROUND: Acute kidney injury (AKI) diagnosis often lacks a baseline serum creatinine (Cr) value. Our study aimed to create a regression equation linking kidney morphology to function in kidney donors and chronic kidney disease patients. We also sought to estimate baseline Cr in minimal change disease (MCD) patients, a common AKI-predisposing condition. METHODS: We analyzed 119 participants (mean age 60 years, 50% male, 40% donors) with CT scans, dividing them into derivation and validation groups. An equation based on kidney parenchymal volume (PV) was developed in the derivation group and validated in the validation group. We estimated baseline Cr in 43 MCD patients (mean age 45 years, 61% male) using the PV-based equation and compared with their 6 month post-MCD onset Cr values. RESULTS: In the derivation group, the equation for the estimated glomerular filtration rate (eGFR) was: eGFR (mL/min/1.73m2) = 0.375 × PV (cm3) + (- 0.395) × age (years) + (- 2.93) × male sex + (- 13.3) × hypertension + (- 14.0) × diabetes + (- 0.210) × height (cm) + 82.0 (intercept). In the validation group, the eGFR and estimated Cr values correlated well with the measured values (r = 0.46, p = 0.01; r = 0.51, p = 0.004, respectively). In the MCD group, the baseline Cr values were significantly correlated with the estimated baseline Cr values (r = 0.52, p < 0.001), effectively diagnosing AKI (kappa = 0.76, p < 0.001). CONCLUSIONS: The PV-based regression equation established in this study holds promise for estimating baseline Cr values and diagnosing AKI in patients with MCD. Further validation in diverse AKI populations is warranted.
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BACKGROUND: Lipoprotein glomerulopathy (LPG) is a apolipoprotein E (ApoE)-related glomerular disease and has been associated with type III hyperlipidemia. Without appropriate treatment, chronic kidney disease (CKD) caused by LPG progresses, and approximately half of the patients develop end-stage kidney disease within 1-27 years of disease onset. However, few studies have highlighted the clinical course of cardiovascular diseases (CVDs) in patients with LPG. Herein, we report the first case of LPG in which the CVD risk was assessed using arterial stiffness. CASE PRESENTATION: A 32-year-old Japanese man was referred to our hospital due to persistent proteinuria. Kidney biopsy showed markedly dilated capillary lumens containing pale-stained thrombi, which stained positively with Oil Red O. Electron microscopy revealed the presence of thrombi in the capillary lumen with low electron density and vacuoles of various sizes in part of the thrombi. Toluidine blue and Sudan IV stains were used to stain the thin sections of Epon-embedded tissue samples for electron microscopy. Sudan IV-positive droplets were observed in the capillary lumens, vascular walls, and cytoplasm of tubular cells. Increased serum ApoE concentration was observed. Liquid chromatography-tandem mass spectrometry of laser-microdissected glomeruli from paraffin sections revealed an increase in ApoE. Direct deoxyribonucleic acid sequencing of ApoE revealed a heterozygous ApoE Sendai mutation (Arg145Pro). The patient was finally diagnosed with LPG with heterozygosity for ApoE-Sendai mutation (Arg145Pro). Notably, at the time of diagnosis, he had markedly increased arterial stiffness for his age. Arterial stiffness was measured using brachial-ankle pulse wave velocity (baPWV), which was equivalent to that of a 56-year-old man. After three months of treatment with fenofibrate and losartan, a significant reduction in proteinuria was achieved along with an improvement in baPWV. Furthermore, these effects were maintained despite the lack of decrease in serum ApoE levels. CONCLUSION: Herein, we report the case of a patient with LPG with markedly increased arterial stiffness at the time of diagnosis, in whom combination therapy with fenofibrate and losartan successfully improved proteinuria and arterial stiffness. To the best of our knowledge, this is the first case report of LPG in which CVD risk was assessed using arterial stiffness.
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Fenofibrato , Losartán , Rigidez Vascular , Humanos , Masculino , Adulto , Losartán/uso terapéutico , Rigidez Vascular/efectos de los fármacos , Fenofibrato/uso terapéutico , Quimioterapia Combinada , Hipolipemiantes/uso terapéutico , Enfermedades Renales/tratamiento farmacológico , Apolipoproteínas E/genéticaRESUMEN
Podocyte loss and resultant nephron loss are common processes in the development of glomerulosclerosis and chronic kidney disease. While the cortical distribution of glomerulosclerosis is known to be non-uniform, the relationship between the numbers of non-sclerotic glomeruli (NSG), podometrics and zonal differences in podometrics remain incompletely understood. To help define this, we studied autopsy kidneys from 50 adults with median age 68 years and median eGFR 73.5 mL/min/1.73m2 without apparent glomerular disease in a cross-sectional analysis. The number of NSG per kidney was estimated using the physical dissector/fractionator combination, while podometrics were estimated using model-based stereology. The number of NSG per kidney was directly correlated with podocyte number per tuft and podocyte density. Each additional 100,000 NSG per kidney was associated with 26 more podocytes per glomerulus and 16 podocytes per 106 µm3 increase in podocyte density. These associations were independent of clinical factors and cortical zone. While podocyte number per glomerulus was similar in the three zones, superficial glomeruli were the smallest and had the highest podocyte density but smallest podocytes. Increasing age and hypertension were associated with lower podocyte number, with age mostly affecting superficial glomeruli, and hypertension mostly affecting juxtamedullary glomeruli. Thus, in this first study to report a direct correlation between the number of NSG and podometrics, we suggest that podocyte number is decreasing in NSG of individuals losing nephrons. However, another possible interpretation may be that more nephrons might protect against further podocyte loss.
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Hipertensión , Podocitos , Adulto , Humanos , Anciano , Estudios Transversales , Glomérulos Renales , RiñónRESUMEN
Although activation of the renin-angiotensin system and of its glomerular components is implicated in the pathogenesis of diabetic nephropathy, the functional roles of the tubular renin-angiotensin system with AT1 receptor signaling in diabetic nephropathy are unclear. Tissue hyperactivity of the renin-angiotensin system is inhibited by the angiotensin II type 1 receptor-associated protein ATRAP, which negatively regulates receptor signaling. The highest expression of endogenous ATRAP occurs in the kidney, where it is mainly expressed by tubules but rarely in glomeruli. Here, we found that hyperactivation of angiotensin II type 1 receptor signaling in kidney tubules exacerbated diabetic glomerular injury in a mouse model of streptozotocin-induced diabetic nephropathy. These phenomena were accompanied by decreased expression of CD206, a marker of alternatively activated and tissue-reparative M2 macrophages, in the kidney tubulointerstitium. Additionally, adoptive transfer of M2- polarized macrophages into diabetic ATRAP-knockout mice ameliorated the glomerular injury. As a possible mechanism, the glomerular mRNA levels of tumor necrosis factor-α and oxidative stress components were increased in diabetic knockout mice compared to non-diabetic knockout mice, but these increases were ameliorated by adoptive transfer. Furthermore, proximal tubule-specific ATRAP downregulation reduced tubulointerstitial expression of CD206, the marker of M2 macrophages in diabetic mice. Thus, our findings indicate that tubular ATRAP-mediated functional modulation of angiotensin II type 1 receptor signaling modulates the accumulation of tubulointerstitial M2 macrophages, thus affecting glomerular manifestations of diabetic nephropathy via tubule-glomerular crosstalk.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Diabetes Mellitus Experimental , Nefropatías Diabéticas , Proteínas Adaptadoras Transductoras de Señales/genética , Angiotensina II/metabolismo , Animales , Diabetes Mellitus Experimental/metabolismo , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/metabolismo , Femenino , Humanos , Riñón/patología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Noqueados , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismo , EstreptozocinaRESUMEN
BACKGROUND: Invasive pulmonary aspergillosis (IPA) is a serious complication occurring in immunocompromised patients, who often show multiple nodular lesions with or without cavitation. Due to high mortality and poor prognosis, the earlier detection and initiation of treatment are needed, while the definitive diagnosis is often difficult to make in clinical settings. Septic pulmonary embolism (SPE) is a complication that occurs in patients with bloodstream infections (e.g., infectious endocarditis). Patients with SPE also present with multiple nodules, nodules with or without cavitation, which are quite similar to the findings of IPA. We herein report an autopsy case that showed multiple nodules due to IPA and infectious endocarditis-related SPE. CASE: A 69-year-old man receiving maintenance hemodialysis due to diabetic nephropathy was admitted with worsening skin rash due to bullous pemphigoid and toxic epidermal necrolysis. He was treated with intravenous methylprednisolone followed by an increased dose of oral prednisolone. On the 6th week of admission, he was diagnosed with infectious endocarditis after the isolation of Corynebacterium in blood samples, with a nodule lesion with cavitation in the right lung. Intravenous vancomycin was initiated. After antibacterial treatment, the nodules in the right lung gradually diminished, whereas a nodule with cavitation in the left lung emerged. The nodule in the left lung showed rapid growth along with elevation of serum ß-D-glucan and galactomannan antigen. Despite starting treatment with antifungal agents, he died from respiratory failure. An autopsy revealed Groccott staining-positive aspergillus in the left lung, but not in the right lung. We found fibrosis with mitral valve vegetation, indicating a recovery from infectious endocarditis. CONCLUSION: Although similar features of nodules with cavitation on CT imaging were shared with SPE and IPA, this case demonstrated that these heterogeneous diseases can occur within the lungs and the distinctly different transitions of CT imaging are helpful for suspecting the presence of multiple pathogeneses.
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Diabetes Mellitus , Endocarditis , Aspergilosis Pulmonar Invasiva , Penfigoide Ampolloso , Corticoesteroides , Anciano , Autopsia , Humanos , Aspergilosis Pulmonar Invasiva/complicaciones , Aspergilosis Pulmonar Invasiva/diagnóstico , Aspergilosis Pulmonar Invasiva/tratamiento farmacológico , Masculino , Metilprednisolona , Penfigoide Ampolloso/diagnóstico , Penfigoide Ampolloso/tratamiento farmacológicoRESUMEN
BACKGROUND: Tubulointerstitial nephritis (TIN) is an important cause of acute kidney injury (AKI) and advanced CKD. Only a limited number of studies have reported etiology-based differences in the clinical and/or histopathological properties and kidney outcomes of the biopsy-proven TIN. METHODS: Patients with biopsy-proven TIN identified from 2005 to 2016 in five hospitals were categorized based on the etiologies and were retrospectively analyzed in relation to the clinicopathological findings and kidney outcomes. RESULTS: Among 4815 biopsy cases screened, 153 Japanese TIN patients were identified, of whom 139 patients with ≥ 6 months of follow-up data (median 58 years old, 45.3% female, median 31.5 months follow-up) were further analyzed. TIN was drug-induced in 32.4%, autoimmune-related in 24.5%, of unknown etiology in 27.3% and other disease-related in 15.8%. Non-steroidal anti-inflammatory drugs and antibiotics were major causative drugs in drug-induced TIN, and IgG4-related disease, Sjögren's syndrome and sarcoidosis were common in autoimmune-related TIN. Among etiology groups, drug-induced TIN showed advanced AKI with elevated serum creatinine (sCr) and increased C-reactive protein levels at the diagnosis. TIN patients with autoimmune diseases showed less-severe AKI, but were more frequently treated with corticosteroids than others. Tubulointerstitial injury expansion in biopsy specimens was comparable among the groups. Complete or partial kidney function recovery at 6 months was more frequent in drug-induced and autoimmune-related TIN than in others. sCr levels at 6 months were similar among the groups. CONCLUSIONS: This largest case series study of the biopsy-proven TIN in Japan provides detailed information regarding both etiology-based clinicopathological properties and kidney outcomes.
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Lesión Renal Aguda , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Nefritis Intersticial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Lesión Renal Aguda/patología , Biopsia , Japón/epidemiología , Riñón , Nefritis Intersticial/inducido químicamente , Nefritis Intersticial/diagnóstico , Nefritis Intersticial/patología , Estudios RetrospectivosRESUMEN
BACKGROUND: Identifying predictive factors for coronavirus disease 2019 (COVID-19) is crucial for risk stratification and intervention. Kidney dysfunction contributes to the severity of various infectious diseases. However, the association between on-admission kidney dysfunction and the clinical outcome in COVID-19 patients is unclear. METHODS: This study was a multicenter retrospective observational cohort study of COVID-19 patients, diagnosed by polymerase chain reaction. We retrospectively analyzed 500 COVID-19 patients (mean age: 51 ± 19 years) admitted to eight hospitals in Japan. Kidney dysfunction was defined as a reduced estimated glomerular filtration rate (< 60 mL/min/1.73 m2) or proteinuria (≥ 1 + dipstick proteinuria) on admission. The primary composite outcome included in-hospital death, extracorporeal membrane oxygenation, mechanical ventilation (invasive and noninvasive methods), and intensive care unit (ICU) admission. RESULTS: Overall, 171 (34.2%) patients presented with on-admission kidney dysfunction, and the primary composite outcome was observed in 60 (12.0%) patients. Patients with kidney dysfunction showed higher rates of in-hospital death (12.3 vs. 1.2%), mechanical ventilation (13.5 vs. 4.0%), and ICU admission (18.1 vs. 5.2%) than those without it. Categorical and multivariate regression analyses revealed that kidney dysfunction was substantially associated with the primary composite outcome. Thus, on-admission kidney dysfunction was common in COVID-19 patients. Furthermore, it correlated significantly and positively with COVID-19 severity and mortality. CONCLUSIONS: On-admission kidney dysfunction was associated with disease severity and poor short-term prognosis in patients with COVID-19. Thus, on-admission kidney dysfunction has the potential to stratify risks in COVID-19 patients.
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COVID-19 , Insuficiencia Renal Crónica , Adulto , Anciano , COVID-19/epidemiología , COVID-19/terapia , Mortalidad Hospitalaria , Humanos , Unidades de Cuidados Intensivos , Japón/epidemiología , Persona de Mediana Edad , Proteinuria , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/terapia , Estudios Retrospectivos , Factores de Riesgo , SARS-CoV-2RESUMEN
BACKGROUND: Podocyte depletion, low nephron number, aging, and hypertension are associated with glomerulosclerosis and CKD. However, the relationship between podometrics and nephron number has not previously been examined. METHODS: To investigate podometrics and nephron number in healthy Japanese individuals, a population characterized by a relatively low nephron number, we immunostained single paraffin sections from 30 Japanese living-kidney donors (median age, 57 years) with podocyte-specific markers and analyzed images obtained with confocal microscopy. We used model-based stereology to estimate podometrics, and a combined enhanced-computed tomography/biopsy-specimen stereology method to estimate nephron number. RESULTS: The median number of nonsclerotic nephrons per kidney was 659,000 (interquartile range [IQR], 564,000-825,000). The median podocyte number and podocyte density were 518 (IQR, 428-601) per tuft and 219 (IQR, 180-253) per 106µm3, respectively; these values are similar to those previously reported for other races. Total podocyte number per kidney (obtained by multiplying the individual number of nonsclerotic glomeruli by podocyte number per glomerulus) was 376 million (IQR, 259-449 million) and ranged 7.4-fold between donors. On average, these healthy kidneys lost 5.63 million podocytes per kidney per year, with most of this loss associated with glomerular loss resulting from global glomerulosclerosis, rather than podocyte loss from healthy glomeruli. Hypertension was associated with lower podocyte density and larger podocyte volume, independent of age. CONCLUSIONS: Estimation of the number of nephrons, podocytes, and other podometric parameters in individual kidneys provides new insights into the relationships between these parameters, age, and hypertension in the kidney. This approach might be of considerable value in evaluating the kidney in health and disease.
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Hipertensión/patología , Glomérulos Renales/patología , Trasplante de Riñón , Donadores Vivos , Podocitos/patología , Factores de Edad , Anciano , Estudios de Casos y Controles , Recuento de Células , Femenino , Humanos , Japón , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis usually induces rapidly progressive glomerulonephritis, including pauci-immune necrotizing crescentic glomerulonephritis. Acute tubulointerstitial nephritis (ATIN), which is often drug-induced, is a frequent cause of kidney injury. However, ATIN associated with ANCA without any glomerular lesions has been rarely reported, and drug-induced ATIN associated with ANCA is not well recognized. Here we present a case of an older woman with ATIN associated with myeloperoxidase-ANCA (MPO-ANCA) following cimetidine treatment. CASE PRESENTATION: A 70-year-old woman was admitted to our hospital due to acute kidney injury and mild proteinuria. She had a one-year history of chronic thyroiditis and dyslipidemia, for which she was taking levothyroxine sodium and atorvastatin, respectively. Two weeks before admission she had started cimetidine, methylmethionine sulfonium chloride, and itopride hydrochloride for gastric discomfort persistent since a month. She had experienced fatigue for two weeks and later appetite loss. The patient demonstrated a positive titer for MPO-ANCA (192 IU/mL) and a positive drug-induced lymphocyte stimulation test for cimetidine. She underwent two kidney biopsies that revealed ATIN without any glomerular lesions. Despite discontinuation of cimetidine on admission, renal injury continued with the presence of high MPO-ANCA titer. Oral steroid treatment was closely related with the recovery of her renal function and disappearance of MPO-ANCA. CONCLUSIONS: In this case, ATIN presented as sustained renal insufficiency and high MPO-ANCA titer despite withdrawal of cimetidine. Therefore, we reason that the development of ANCA-associated ATIN was caused by cimetidine. Serologic follow-up with measurement of MPO-ANCA titers and renal biopsy are recommended when the clinical history is inconsistent with the relatively benign course of drug-induced ATIN.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inducido químicamente , Anticuerpos Anticitoplasma de Neutrófilos/sangre , Cimetidina/efectos adversos , Inhibidores del Citocromo P-450 CYP1A2/efectos adversos , Nefritis Intersticial/inducido químicamente , Adulto , Anciano , Femenino , Humanos , Riñón/patología , Masculino , Persona de Mediana Edad , Nefritis Intersticial/patologíaRESUMEN
BACKGROUND: Heavy proteinuria at diagnostic renal biopsy has been reported as an independent risk factor for deteriorating renal function in benign nephrosclerosis (BNS). However, studies investigating the relationship between the amount of proteinuria during follow-up and long-term renal prognosis in BNS are limited. This study aimed to assess the relationship between time-averaged proteinuria (TAP) and renal prognosis in BNS. METHODS: The study participants included 98 patients with biopsy-proven BNS (average age 52 ± 13 years, estimated glomerular filtration rate (eGFR) 53 ± 25 ml/min/1.73 m2, urine protein excretion at baseline 1.34 ± 1.30 g/gCr) from the Jikei University Hospital. Multivariate analysis was used to investigate the effects of TAP and other clinicopathological findings on the risk for renal outcome in biopsy-proven BNS (a 30% decline in eGFR from baseline or end-stage renal disease). Proteinuria was measured every 6 months and the mean value was used as an indicator of TAP. RESULTS: The average observation period was 56 ± 43 months. In the unadjusted model, higher levels of TAP and urinary protein at baseline, glomerulosclerosis, and tubulointerstitial damage were associated with renal prognosis. The adjusted model demonstrated a significant association between TAP and renal outcomes (hazard ratio 5.45, 95% confidence interval 3.02-10.7), which was independent of higher baseline proteinuria, glomerulosclerosis, and tubulointerstitial damage. CONCLUSIONS: TAP is an independent risk factor for renal prognosis in patients with BNS, indicating the significance of urinary protein excretion during follow-up for the progression of BNS. Clinicians should understand the importance of follow-up evaluation for proteinuria in patients with BNS.
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Nefroesclerosis/orina , Proteinuria/diagnóstico , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios RetrospectivosRESUMEN
AbstractsBackground: Recent studies have identified the significance of proteinuria levels after initial induction therapies on the renal outcomes in patients with proliferative lupus nephritis, but the issue has not been evaluated in Japanese patients.Methods: Based on the ISN/RPS classification, only patients diagnosed with lupus nephritis class III or IV were included. The remission of proteinuria 12 months after diagnosis, as well as the clinicopathological features at diagnosis, on renal outcomes was examined retrospectively. Renal progression was defined as a 50% decrease in the estimated glomerular filtration rate or the development of end-stage renal disease.Results: This study included 82 Japanese patients with a median follow-up period of seven years. Although all patients received intensive induction therapy, 15 patients (18%) showed progression. Proteinuric remission 12 months after diagnosis predicted a good renal outcome by multivariate analysis. A receiver-operating characteristic analysis of 38 patients whose quantitative urinary protein excretion levels at 12 months were available for analysis showed that a cut-off value of 0.8 g/day predicted renal progression most effectively. Neither the renal function nor proteinuria level at diagnosis were associated with the renal outcomes.Conclusion: In Japanese patients with lupus nephritis class III or IV, proteinuria levels after 12 months under intensive therapy predicted renal outcomes more accurately than did factors identified at diagnosis.
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Glucocorticoides/uso terapéutico , Inmunosupresores/uso terapéutico , Riñón/patología , Nefritis Lúpica/terapia , Proteinuria/terapia , Inducción de Remisión/métodos , Adolescente , Adulto , Anciano , Biopsia , Niño , Progresión de la Enfermedad , Femenino , Tasa de Filtración Glomerular , Humanos , Incidencia , Japón/epidemiología , Riñón/fisiopatología , Nefritis Lúpica/complicaciones , Nefritis Lúpica/diagnóstico , Masculino , Persona de Mediana Edad , Proteinuria/epidemiología , Proteinuria/etiología , Curva ROC , Estudios Retrospectivos , Adulto JovenRESUMEN
Innate lymphoid cells play an important role in the early effector cytokine-mediated response. In Wistar Kyoto rats, CD8+ non-T lymphocytes (CD8+Lym) infiltrate into glomeruli during the development of anti-glomerular basement membrane (anti-GBM) glomerulonephritis. Here, we examined the profiles and roles of CD8+Lym in anti-GBM glomerulonephritis. The regulation of CD8+Lym by peroxisome proliferator-activated receptor (PPAR)-α in anti-GBM glomerulonephritis was also evaluated. Glomerular infiltrating CD8+Lym were lineage-negative cells that showed markedly high expression of IFN-γ and T-bet mRNAs but not Eomes, indicating these cells are group 1 innate lymphoid cells. In anti-GBM glomerulonephritis, the glomerular mRNAs of innate lymphoid cell-related cytokines (IFN-γ and TNF-α) and chemokines (CXCL9, CXCL10, and CXCL11) are significantly increased. Treatment with a PPARα agonist ameliorated renal injury, with reduced expression of these mRNAs. In vitro, enhanced IFN-γ production from innate lymphoid cells upon IL-12 and IL-18 stimulation was reduced by the PPARα agonist. Moreover, CXCL9 mRNA in glomerular endothelial cells and CXCL9, CXCL10, and CXCL11 mRNAs in podocytes and macrophages were upregulated by IFN-γ, whereas the PPARα agonist downregulated their expression. We also detected the infiltration of innate lymphoid cells into glomeruli in human anti-GBM glomerulonephritis. Thus, innate lymphoid cells are involved in the progression of anti-GBM glomerulonephritis and regulated directly or indirectly by PPARα. Our findings suggest that innate lymphoid cells could serve as novel therapeutic targets for anti-GBM glomerulonephritis.
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Enfermedad por Anticuerpos Antimembrana Basal Glomerular/inmunología , Membrana Basal Glomerular/patología , Inmunidad Innata , Subgrupos Linfocitarios/inmunología , PPAR alfa/metabolismo , Animales , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/tratamiento farmacológico , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/patología , Biopsia , Antígenos CD8/metabolismo , Células Cultivadas , Quimiocinas CXC/inmunología , Quimiocinas CXC/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/inmunología , Fenofibrato/farmacología , Fenofibrato/uso terapéutico , Membrana Basal Glomerular/citología , Membrana Basal Glomerular/inmunología , Humanos , Subgrupos Linfocitarios/metabolismo , Masculino , PPAR alfa/agonistas , Cultivo Primario de Células , RatasRESUMEN
BACKGROUND: Increasing evidence suggests that individuals with low nephron number have an increased lifetime risk of renal insufficiency, thereby emphasizing the importance of evaluating total nephron number in each individual. In recent years, new methods have been described for estimating human total nephron number using a combination of image analysis and renal biopsy, though the reproducibility and accuracy of these methods remain uncertain. This study estimated total nephron number in healthy Japanese subjects using such a method. METHODS: Implantation biopsies from 44 living kidney donors were analyzed. Using pre-donation contrast CT angiograms, transplantation donor kidneys were three-dimensionally reconstructed, and total renal cortical volume was estimated. Total nephron number was estimated based on glomerular density in biopsy specimens and total renal cortical volume. The obtained results were analyzed in relation to clinical variables and compared with those of a previously reported Japanese autopsy study. RESULTS: The estimated non-sclerotic and total numbers of glomeruli in this cohort were 650,000 ± 220,000 and 710,000 ± 220,000 (mean ± SD) per kidney. Non-sclerotic glomerular number ranged from 280,000 to 1,220,000 per kidney (4.4-fold) and correlated directly with eGFR (r = 0.328, p = 0.030) and inversely with age (r = - 0.355, p = 0.018). CONCLUSION: The estimated total nephron number obtained in the present study was 25% less than that reported in American living kidney donors obtained using the same procedure and similar to that obtained in a previous Japanese autopsy study using the disector/fractionator method. These results confirm the feasibility of a combined CT angiography and biopsy-based method to estimate total nephron number in humans.