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INTRODUCTION: Hypertensive nephrosclerosis (HN) ranks as one of the most frequent causes of chronic kidney disease (CKD), but its very existence has repeatedly been called into question, especially in young adults. Its diagnostic framework is established chiefly on non-specific clinical criteria, and its defining histopathological set of features is in fact shared by numerous other conditions. Genetic testing based on exome sequencing (ES) has emerged as a comprehensive tool to detect Mendelian diseases in timely fashion in nephrology, with a significant number of re-established diagnoses. The aim of this study was to investigate the diagnostic yield of ES in patients with a clinical diagnosis of hypertensive nephropathy. METHOD: Since September 2018, ES has been readily available as part of the routine diagnostic work-up in our institution. The indication of ES includes hypertensive nephropathy of early onset (i.e., <45 years old). We retrospectively collected the ES data performed in the context of hypertensive nephropathy in our institution between September 2018 and February 2021. RESULTS: A total of 128 patients were sequenced in the context of hypertensive nephropathy with early onset. The chief indications of ES were an early onset of CKD (47%), family history of kidney disease (8%), or both (18%). We detected diagnostic variants in 19 of the 128 patients (15%), encompassing a total of 13 different monogenic disorders. The diagnostic yield of ES was lower in patients of African ancestry (diagnostic yield of 7 vs. 30% in non-African ancestry patients, p < 0.001). CONCLUSIONS: The high diagnostic yield of ES (15%) in a population of patients thought to have HN casts further doubts on the validity of the existing diagnosis criteria, including histological criteria, supposed to characterize the condition. This was especially true in patients with no African ancestry, where ES positivity reached 30%.
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Secuenciación del Exoma , Hipertensión Renal , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Estudios Retrospectivos , Hipertensión Renal/genética , Hipertensión Renal/diagnóstico , Edad de Inicio , Nefritis/genética , Nefritis/diagnóstico , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/diagnóstico , Nefroesclerosis/genética , Nefroesclerosis/diagnósticoRESUMEN
Acute kidney injury activates both proliferative and antiproliferative pathways, the consequences of which are not fully elucidated. If an initial proliferation of the renal epithelium is necessary for the successful repair, the persistence of proliferation markers is associated with the occurrence of chronic kidney disease. We hypothesized that proliferation in stress conditions impacts cell viability and renal outcomes. We found that proliferation is associated with cell death after various stresses in kidney cells. In vitro, the ATP/ADP ratio oscillates reproducibly throughout the cell cycle, and cell proliferation is associated with a decreased intracellular ATP/ADP ratio. In vivo, transcriptomic data from transplanted kidneys revealed that proliferation was strongly associated with a decrease in the expression of the mitochondria-encoded genes of the oxidative phosphorylation pathway, but not of the nucleus-encoded ones. These observations suggest that mitochondrial function is a limiting factor for energy production in proliferative kidney cells after injury. The association of increased proliferation and decreased mitochondrial function was indeed associated with poor renal outcomes. In summary, proliferation is an energy-demanding process impairing the cellular ability to cope with an injury, highlighting proliferative repair and metabolic recovery as indispensable and interdependent features for successful kidney repair.NEW & NOTEWORTHY ATP depletion is a hallmark of acute kidney injury. Proliferation is instrumental to kidney repair. We show that ATP levels vary during the cell cycle and that proliferation sensitizes renal epithelial cells to superimposed injuries in vitro. More proliferation and less energy production by the mitochondria are associated with adverse outcomes in injured kidney allografts. This suggests that controlling the timing of kidney repair might be beneficial to mitigate the extent of acute kidney injury.
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Lesión Renal Aguda , Daño por Reperfusión , Humanos , Riñón/metabolismo , Lesión Renal Aguda/genética , Lesión Renal Aguda/metabolismo , Células Epiteliales/metabolismo , Proliferación Celular , Adenosina Trifosfato/metabolismo , Daño por Reperfusión/metabolismoRESUMEN
Focal segmental glomerulosclerosis (FSGS) is a major cause of end-stage renal disease and remains without specific treatment. To identify new events during FSGS progression, we used an experimental model of FSGS associated with nephroangiosclerosis in rats injected with L-NAME (Nω-nitro-L-arginine methyl ester). After transcriptomic analysis we focused our study on the role of Isthmin-1 (ISM1, an anti-angiogenic protein involved in endothelial cell apoptosis. We studied the renal expression of ISM1 in L-NAME rats and other models of proteinuria, particularly at the glomerular level. In the L-NAME model, withdrawal of the stimulus partially restored basal ISM1 levels, along with an improvement in renal function. In other four animal models of proteinuria, ISM1 was overexpressed and localized in podocytes while the renal function was degraded. Together these facts suggest that the glomerular expression of ISM1 correlates directly with the progression-recovery of the disease. Further in vitro experiments demonstrated that ISM1 co-localized with its receptors GRP78 and integrin αvß5 on podocytes. Treatment of human podocytes with low doses of recombinant ISM1 decreased cell viability and induced caspase activation. Stronger ISM1 stimuli in podocytes dropped mitochondrial membrane potential and induced nuclear translocation of apoptosis-inducing factor (AIF). Our results suggest that ISM1 participates in the progression of glomerular diseases and promotes podocyte apoptosis in two different complementary ways: one caspase-dependent and one caspase-independent associated with mitochondrial destabilization.
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Glomeruloesclerosis Focal y Segmentaria , Podocitos , Animales , Humanos , Ratas , Inhibidores de la Angiogénesis/uso terapéutico , Caspasas/metabolismo , Modelos Animales de Enfermedad , Glomeruloesclerosis Focal y Segmentaria/metabolismo , NG-Nitroarginina Metil Éster/metabolismo , Podocitos/metabolismo , Proteinuria/metabolismoRESUMEN
BACKGROUND: Tumor lysis syndrome (TLS) is a life-threatening complication during the treatment of malignant neoplasia. We sought to describe characteristics and predictors of acute kidney injury (AKI), remission and mortality in high-risk TLS patients. In this retrospective monocentric study, we included all patients with the diagnosis of biological and/or clinical TLS from 2012 to 2018. The primary outcome was the prevalence of AKI during the acute phase of TLS. Secondary outcomes were overall mortality and remission of the underlying malignancy at 1 year. RESULTS: Among 153 patients with TLS, 123 (80.4%) patients experienced AKI and 83 (54.2%) required renal replacement therapy. mSOFA score (OR = 1.15, IC 95% [1.02-1.34]), age (OR = 1.05, IC 95% [1.02-1.08]) and male gender (OR = 6.79, IC 95% [2.59-19.44]) were associated with AKI. Rasburicase use (HR = 2.45, IC 95% [1.17-5.15]) was associated with remission of the underlying malignancy at 1 year. Parameters associated with mortality at 1 year were mechanical ventilation (HR = 1.96, IC 95% [1.02-3.78]), vasopressors (HR = 3.13, IC 95% [1.59-6.15]), age (HR = 1.02, IC 95% [1-1.03]), spontaneous TLS (HR = 1.65, IC 95% [1.01-2.69]) and delay of chemotherapy administration (HR = 1.01, IC 95% [1-1.03]). CONCLUSIONS: AKI is highly prevalent in TLS patients. Rasburicase is associated with better outcomes regarding remission of the underlying malignancy. As rasburicase may be an indirect marker of a high degree of tumor lysis and chemosensitivity, more studies are warranted to confirm the protective role of urate oxidase. Delaying chemotherapy may be deleterious in terms of long-term outcomes.
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Hydroxychloroquine (HCQ) is largely prescribed as an immunomodulator to prevent systemic diseases flares in patients with systemic lupus erythematous, rheumatoid arthritis, Sjogren's disease. Among reported side effects, HCQ can accumulate in lysosomes and induced phospholipidosis. Here, we report an HCQ-induced podocytopathy mimicking Fabry disease (FD). They share the same histological lesions: cytoplasmic vacuolisation of the podocytes and zebra bodies on light and electronic microscopy. FD has been ruled out by measuring enzymatic activity and genetic test. The persistence of proteinuria after immunological remission of a systemic disease treated with HCQ could suggest this HCQ-induced podocytopathy.