RESUMEN
Mineralocorticoid receptor antagonists (MRAs) are one of the renin-angiotensin-aldosterone system inhibitors widely used in clinical practice. While spironolactone and eplerenone have a long-standing profile in clinical medicine, finerenone is a novel agent within the MRA class. It has a higher specificity for mineralocorticoid receptors, eliciting less pronounced adverse effects. Although approved for clinical use in patients with chronic kidney disease and heart failure, intensive non-clinical research aims to further elucidate its mechanism of action, including dose-related selectivity. Within the field, animal models remain the gold standard for non-clinical testing of drug pharmacological and toxicological properties. Their role, however, has been challenged by recent advances in in vitro models, mainly through sophisticated analytical tools and developments in data analysis. Currently, in vitro models are gaining momentum as possible platforms for advanced pharmacological and pathophysiological studies. This article focuses on past, current, and possibly future in vitro cell models research with clinically relevant MRAs.
Asunto(s)
Antagonistas de Receptores de Mineralocorticoides , Receptores de Mineralocorticoides , Antagonistas de Receptores de Mineralocorticoides/farmacología , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Humanos , Animales , Receptores de Mineralocorticoides/metabolismo , Espironolactona/farmacología , Espironolactona/análogos & derivados , Espironolactona/uso terapéutico , Eplerenona/farmacología , Eplerenona/uso terapéutico , Naftiridinas/farmacología , Evaluación Preclínica de Medicamentos/métodos , Sistema Renina-Angiotensina/efectos de los fármacos , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismoRESUMEN
The kidneys are the body's main excretion organ with several additional functions, and the nephron represents their central structural unit. It is comprised of endothelial, mesangial, glomerular, and tubular epithelial cells, as well as podocytes. Treatment of acute kidney injury or chronic kidney disease (CKD) is complex due to broad etiopathogenic mechanisms and limited regeneration potential as kidney cells finish their differentiation after 34 weeks of gestation. Despite the ever-increasing prevalence of CKD, very limited treatment modalities are available. The medical community should therefore strive to improve existing treatments and develop new ones. Furthermore, polypharmacy is present in most CKD patients, while current pharmacologic study designs lack effectiveness in predicting potential drug-drug interactions and the resulting clinically relevant complications. An opportunity for addressing these issues lies in developing in vitro cell models based on patient-derived renal cells. Currently, several protocols have been described for isolating desired kidney cells, of which the most isolated are the proximal tubular epithelial cells. These play a significant role in water homeostasis, acid-base control, reabsorption of compounds, and secretion of xenobiotics and endogenous metabolites. When developing a protocol for the isolation and culture of such cells, one must focus on several steps. These include harvesting cells from biopsy specimens or after nephrectomies, using different digestion enzymes and culture mediums to facilitate the selective growth of only the desired cells. The literature reports several existing models, from simple 2D in vitro cultures to more complex ones created with bioengineering methods, such as kidney-on-a-chip models. While their creation and use depend on the target research, one should consider factors such as equipment, cost, and, even more importantly, source tissue quality and availability.
Asunto(s)
Podocitos , Insuficiencia Renal Crónica , Humanos , Riñón/patología , Células Epiteliales/patología , Insuficiencia Renal Crónica/patología , Glomérulos Renales/patología , Podocitos/patologíaRESUMEN
BACKGROUND: Monitoring of arteriovenous (AV) fistula to detect hemodynamically important stenosis is crucial for the prevention of AV fistula thrombosis. The aim of our study was to analyze the importance of dialysis dose (Kt/V) during online postdilution hemodiafiltration (HDF) for early detection of AV fistula stenosis. METHODS: Hemodialysis patients with AV fistula were included in this study. We compared a group of 44 patients who have undergone fistulography and subsequently percutaneous transluminal angioplasty (PTA) of significant AV fistula stenosis (active group) with a group of 44 age- and sex-matched patients without PTA (control group). Observational time in both groups was the same. RESULTS: All patients had postdilution online HDF using a F5008 dialysis machine, which can measure online single-pool Kt/V. All data were analyzed during the performance of 2056 HDF procedures. In the active group, we found statistically significantly lower values of Kt/V, all 8 weeks before PTA. In the active group, there was a significant improvement in Kt/V in the first (p < 0.001) and second week (p = 0.049) after PTA. Three and 8 weeks after PTA, we did not find any statistically significant difference in Kt/V between both groups (p = 0.114; p = 0.058). Patients in the active group had statistically significantly lower substitution volumes and blood pump flow rates during HDF over the whole observation period before and after PTA. In contrast, there were no differences in venous pressure in the dialysis circuit between both groups throughout the observation period. CONCLUSION: In hemodialysis patients with AV fistula, treated with online HDF, routine measurements of Kt/V during each HDF are a beneficial, quick, and straightforward method for early detection of hemodynamically significant AV fistula stenosis.