Role of aliskiren in blood pressure control and renoprotection

Patients with chronic renal disease are at increased risk for the development of cardiovascular disease, which is the main cause of death in this growing population. Among the risk factors involved, hypertension and proteinuria are major contributors to kidney damage and, if not controlled, may eventually lead to the progression of renal failure and end-stage renal disease. Both proteinuria and hypertension can be primary pathologic events or can appear as complications of other disease processes. Initially, these two factors may operate separately but, as progression ensues, both processes generally combine, potentiating their effects and hastening renal damage. Therefore, strategies to reduce blood pressure and proteinuria are essential in order to slow the worsening of many nephropathies. Therapies that target the renin–angiotensin system offer particular benefit, as hypertension and proteinuria can be precisely reduced with angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers. However, with this intervention, plasma renin activity remains high, and although primary endpoints may be controlled, elevated renin concentration can contribute to cardiovascular damage. Aliskiren, a direct renin inhibitor, is the first example of a novel class of antihypertensive drugs with potent antiproteinuric effects, which, alone or combined, can contribute to delaying the progression of kidney disease

Is There a Role for Mammalian Target of Rapamycin Inhibition in Renal Failure due to Mesangioproliferative Nephrotic Syndrome?

Primary glomerulonephritis stands as the third most important cause of end-stage renal disease, suggesting that appropriate treatment may not be as effective as intended to be. Moreover, proteinuria, the hallmark of glomerular damage and a prognostic marker of renal damage progression, is frequently resistant to thorough control. In addition, proteinuria may be the common end pathway in which different pathogenetic mechanisms may converge. This explains why immunosuppressive and nonimmunosuppressive approaches are partly not sufficient to halt disease progression. One of the commonest causes of primary glomerulonephritis is mesangioproliferative glomerulonephritis. Among the triggered intracellular pathways involved in mesangial cell proliferation, the mammalian target of rapamycin (mTOR) plays a critical role in cell growth, in turn regulated by many cytokines, disbalanced by the altered glomerulopathy itself. However, when inhibition of mTOR was studied in rodents and in humans with primary glomerulonephritis the results were contradictory. In light of these controversial data, we propose an explanation for these results, to dilucidate under which circumstances mTOR inhibition should be considered to treat glomerular proteinuria and finally to propose mTOR inhibitors to be prospectively assessed in clinical trials in patients with primary mesangioproliferative glomerulonephritis, for which a satisfactory standard immunosuppressive regimen is still pending

Fabry disease and COVID-19: International expert recommendations for management based on real-world experience

The rapid spread of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 has raised questions about Fabry disease (FD) as an independent risk factor for severe COVID-19 symptoms. Available real-world data on 22 patients from an international group of healthcare providers reveals that most patients with FD experience mild-to-moderate COVID-19 symptoms with an additional complication of Fabry pain crises and transient worsening of kidney function in some cases; however, two patients over the age of 55 years with renal or cardiac disease experienced critical COVID-19 complications. These outcomes support the theory that pre-existent tissue injury and inflammation may predispose patients with more advanced FD to a more severe course of COVID-19, while less advanced FD patients do not appear to be more susceptible than the general population. Given these observed risk factors, it is best to reinforce all recommended safety precautions for individuals with advanced FD. Diagnosis of FD should not preclude providing full therapeutic and organ support as needed for patients with FD and severe or critical COVID-19, although a FD-specific safety profile review should always be conducted prior to initiating COVID-19-specific therapies. Continued specific FD therapy with enzyme replacement therapy, chaperone therapy, dialysis, renin–angiotensin blockers or participation to clinical trials during the pandemic is recommended as FD progression will only increase susceptibility to infection. In order to compile outcome data and inform best practices, an international registry for patients affected by Fabry and infected by COVID-19 should be established

Consenso de expertos sobre recomendaciones basadas en evidencia para el diagnóstico, tratamiento y seguimiento de enfermedad de Fabry en pediatría

Antecedentes: La enfermedad de Fabry (EF) es una enfermedad rara ligada a X secundaria al depósito lisosomal de glicoesfingolípidos debido a la deficiencia de la enzima alfa galactosidasa A (α-Gal A). A pesar de su baja frecuencia, es una condición que afecta la calidad de vida de los pacientes y disminuye su esperanza de vida. Objetivo: Generar recomendaciones informadas en evidencia para el diagnóstico y tratamiento de pacientes pediátricos (menores de 8 años) con EF. Métodos: Se realizó una revisión de literatura en bases de datos y literatura gris a partir del 2010, incluyendo guías de práctica clínica, revisiones sistemáticas, estudios primarios. La calidad de evidencia se evalúo de acuerdo con el tipo de evidencia. Las recomendaciones se sometieron a consenso de expertos a través de metodología Delphi modificada. El acuerdo se definió a partir del 80%. Resultados: A partir del análisis de la evidencia recolectada, se formularon un total de 45 recomendaciones para tamización, diagnóstico y tratamiento de paciente pediátrico con enfermedad de Fabry. El panel revisor estuvo conformado por once expertos en el tema. Las recomendaciones fueron aprobadas con puntuaciones entre 82.3% y 100%. Conclusiones: Las recomendaciones resultantes del consenso de expertos permitirán la toma de decisiones clínicas y estandarización de la práctica en la atención de pacientes pediátricos con EF a nivel nacional y regional; el diagnóstico temprano y oportuno garantiza una disminución del impacto en la calidad de vida de los pacientes y sus familiares. Palabras clave: Enfermedad de Fabry, niños, diagnóstico, terapeutica, biomarcadore

SARS-CoV-2 and Fabry nephropathy: potential risks and the pathophysiological perspective

Fabry disease is an X-linked disorder due to mutations in alpha-galactosidase A gene. It affects the kidney in virtually all patients with classical and some late onset variants. Podocytes, endothelial cells, vascular smooth muscle, tubular and mesangial cells are involved in different ways. Proteinuria and chronic kidney disease are the result of the progressive accumulation of the enzyme substrates globotriaosylceramide (GB3) and lyso-GB3 in the cytoplasm of these cells (mainly in lysosomes), which leads to cellular and organ dysfunction and eventually renal failure and end-stage kidney disease. Specific enzyme replacement therapy and pharmacological chaperone are at present the main therapeutic approach. After enzyme infusion, the delivered enzyme is differentially uptaken by kidney cells in three different ways: By Mannose-6-phosphate receptor, megalin and sortilin. The delivered enzyme gradually clears cells from the accumulation of the glycosphingolipids and contributes to a cellular healthier status. The recent pandemic caused by SARS-CoV-2 has led to the collapse of health systems around the world and to thousands of deaths. Kidney involvement has been reported to range from proteinuria to acute kidney injury, 30% of which may require renal replacement therapy. In this review the potential causes for which Fabry patients should be at increased risk and the necessity not to discontinue therapy are discussed

Primary Focal Segmental Glomerulosclerosis: Why Are Pieces of This Puzzle Still Missing?

Focal segmental glomerulosclerosis (FSGS) can be classified as primary or secondary. Moreover, many causes of primary FSGS have been identified in recent years. In this regard, genetic circulating permeability factors and the abnormal podocyte expression of co-stimulatory molecules have been reported. However, the classification of this entity remains difficult to understand, mainly due to the fact that it describes a morphologic pattern of scarring. FSGS is a histological pattern shared by almost all the glomerulonephritides that describes a podocyte lesion and not a disease. Therefore, it should be reclassified according to the new pathophysiological findings and the biomarkers encountered in each triggered pathway