Sodium-glucose cotransporter inhibitors : beyond glycaemic control

Diabetes increases the risk of adverse cardiovascular and renal events. Recently, sodium-glucose co-transporter 2 (SGLT2) inhibitors have been demonstrated to reduce cardiovascular complications and slow diabetic kidney disease progression in patients with type 2 diabetes. The glycaemic control exerted by these drugs is not greater than the one achieved with other classical glucose-lowering medications such as sulphonylureas. For that reason, plausible renoprotective mechanisms independent from glycaemic control have been proposed such as blood pressure control, body weight loss, intraglomerular pressure reduction and a decrease in urinary proximal tubular injury biomarkers. Interestingly, the hypothesis that SGLT2 inhibitors have a direct renoprotective effect has been addressed in diabetic and non-diabetic models. In this editorial, we update the different postulated mechanisms involved in the cardiorenal protection afforded by SGLT2 inhibition in chronic kidney disease

Sodium-glucose cotransporter 2 inhibition: towards an indication to treat diabetic kidney disease

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have clearly demonstrated their beneficial effect in diabetic kidney disease (DKD) on top of the standard of care [blood glucose control, renin-angiotensin system blockade, smoking cessation and blood pressure (BP) control], even in patients with overt DKD. However, the indication of this drug class is still blood glucose lowering in type 2 diabetic patients with estimated glomerular filtration rate >45mL/min/1.73m(2). Based on the new evidence, several scientific societies have emphasized the preferential prescription of SGLT2i for patients at risk of heart failure or kidney disease, but still within the limits set by health authorities. A rapid positioning of both the European Medicines Agency and the US Food and Drug Administration will allow patients with overt DKD to benefit from SGLT2i. Clinical experience suggests that SGLT2i safety management may in part mirror renin-angiotensin blockade safety management in patients with overt DKD. This review focuses on the rationale for an indication of SGTL2i in DKD. We further propose clinical steps for maximizing the safety of SGLT2i in DKD patients on other antidiabetic, BP or diuretic medication

Exploring Sodium Glucose Co-Transporter-2 (SGLT2) Inhibitors for Organ Protection in COVID-19

Hospital admissions and mortality from the Coronavirus disease 2019 (COVID-19) pandemic are spreading throughout the world, and second and third waves are thought to be likely. Risk factors for severe COVID-19 include diabetes, chronic kidney disease and cardiovascular disease. Currently, there is no vaccine and no approved therapy. Therapeutic approaches are aimed at preventing viral replication and spread, limiting the impact of the inflammatory overdrive (cytokine storm), preventing thromboembolic complications and replacing or supporting organ function. However, despite organ support, mortality is currently 65% for those receiving advanced respiratory support and 78% for those requiring renal replacement therapies. Thus, efforts should be made to provide adjuvant organ protection therapy. This may imply novel therapies in clinical development (e.g., the Fas ligand trap asunercept), but uptake of repurposed drugs already in clinical use may be faster. In this regard, sodium glucose co-transporter-2 (SGLT2) inhibitors were recently shown to protect the heart and kidney both within and outside of a diabetic milieu context. Further, preclinical data support a beneficial effect for the lung. We now discuss the potential benefits and risks of SGLT2 inhibitors in COVID-19 and an ongoing clinical trial testing the impact of dapagliflozin on outcomes in COVID-19 patients with respiratory failure

Challenges in primary focal segmental glomerulosclerosis diagnosis : from the diagnostic algorithm to novel biomarkers

Primary or idiopathic focal segmental glomerulosclerosis (FSGS) is a kidney entity that involves the podocytes, leading to heavy proteinuria and in many cases progresses to end-stage renal disease. Idiopathic FSGS has a bad prognosis, as it involves young individuals who, in a considerably high proportion (∼15%), are resistant to corticosteroids and other immunosuppressive treatments as well. Moreover, the disease recurs in 30-50% of patients after kidney transplantation, leading to graft function impairment. It is suspected that this relapsing disease is caused by a circulating factor(s) that would permeabilize the glomerular filtration barrier. However, the exact pathologic mechanism is an unsettled issue. Besides its poor outcome, a major concern of primary FSGS is the complexity to confirm the diagnosis, as it can be confused with other variants or secondary forms of FSGS and also with other glomerular diseases, such as minimal change disease. New efforts to optimize the diagnostic approach are arising to improve knowledge in well-defined primary FSGS cohorts of patients. Follow-up of properly classified primary FSGS patients will allow risk stratification for predicting the response to different treatments. In this review we will focus on the diagnostic algorithm used in idiopathic FSGS both in native kidneys and in disease recurrence after kidney transplantation. We will emphasize those potential confusing factors as well as their detection and prevention. In addition, we will also provide an overview of ongoing studies that recruit large cohorts of glomerulopathy patients (Nephrotic Syndrome Study Network and Cure Glomerulonephropathy, among others) and the experimental studies performed to find novel reliable biomarkers to detect primary FSGS

Identificació de biomarcadors precoços de nefrotoxicitat induïda per fàrmacs anticalcineurínics

El transplantament renal ha suposat una millora significativa de la qualitat de vida dels pacients amb dany renal crònic. Tot i això, l’empelt acaba perdent funcionalitat i es desenvolupa una patologia anomenada nefropatia crònica de l'empelt (CAN). Les causes d’aquesta patologia poden ser el rebuig immunològic de l’empelt renal o d’altres lesions com les causades per la isquèmia-reperfusió pròpies del procés quirúrgic o les degudes al propi tractament immunosupressor amb fàrmacs anticalcineuríncs (CNIs), Ciclosporina A (CsA) o FK-506. Els mètodes de mesura de la funció renal tradicionals com ara els nivells de creatinina en sèrum i la taxa de filtració glomerular, no permeten fer un diagnòstic de disfunció renal a l’inici i precís que permeti distingir el dany causat per factors immunològics dels no immunològics, com per exemple la nefrotoxicitat per fàrmacs CNIs. Per aquest motiu, l’objectiu d’aquesta tesi és la identificació de proteïnes diferencialment secretades per cèl•lules tubulars humanes en cultiu sotmeses a diferents noxes en condicions subtòxiques (CsA, FK506, Rapamicina i Staurosporina). La hipòtesi de treball és que, potencialment, aquestes proteïnes podrien ser detectades en sang i orina de pacient trasplantats i ser útils com a biomarcadors primerencs específics de la nefrotoxicitat causada per fàrmacs CNIs. S'han obtingut mapes proteòmics de les proteïnes secretades (secretomes) en cada condició subtòxica i s’han determinat les proteïnes diferencialment secretades en cada cas. Entre les proteïnes específicament secretades per CsA i/o FK-506 hem analitzat la vàlua de dues d’elles com a biomarcador de dany renal per CNIs: Plasminogen activator-inhibitor-1 (PAI-1), diferencialment secretada per CsA, i Fascina-1, secretada per efecte d’ambdós fàrmacs CNIs. La mesura dels nivells de PAI-1 en sang i orina de pacients trasplantats de ronyó no ha resultat ser útil per detectar dany renal per fàrmacs CNIs. En canvi, hem observat que l’aparició de Fascina-1 en orina de pacients trasplantats de ronyó i de pulmó sembla indicar disfunció renal precoç produïda per fàrmacs CNIs. També, hem detectat Fascina-1 en exosomes urinaris de pacients trasplantats de ronyó fet que permet explicar l’aparició d’una proteïna dels citoesquelet al medi extracel•lular. Els resultats obtinguts suggereixen que l’alliberació al medi de Fascina-1 induïda per fàrmacs CNIs és depenent de l’activació de la proteïna quinasa C.Renal transplantation has led to a significant improvement in the quality of life of patients with chronic kidney disease. However, over the years the graft loses functionality and develops a pathology called Chronic Allograft Nephropathy (CAN). The causes of this condition can be immune rejection of the graft or other injuries such as those caused by ischemia-reperfusion resulting from the surgical procedure itself or due to the Calcineurin Inhibitor (CNI) immunosuppressive treatment with Cyclosporine A (CsA) or FK-506. The traditional methods of measurement of renal function such as serum levels of creatinine and glomerular filtration rate, do not allow a diagnosis of renal dysfunction at the beginning and accurate enough to distinguish between the damage caused by immunological and non immunological factors such as CNI induced nephrotoxicity. For this reason, the aim of this thesis is the identification of proteins differentially secreted by human tubular cells in culture under different noxious treatments (CsA, FK506, Rapamycin and Staurosporine) at sublethal conditions. The working hypothesis is that, potentially, these proteins could be detected in blood or urine of transplanted patients and be useful as specific biomarkers of early nephrotoxicity caused by CNIs. Proteomic maps were obtained of secreted proteins (secretome) in each sublethal condition and differentially secreted proteins were determined in each case. Among the proteins specifically secreted by CsA and/or FK-506 we have analyzed the value of two of them as a biomarker of CNI induced kidney damage: Plasminogen activator inhibitor-1 (PAI-1), differentially secreted by CsA, and Fascin-1, secreted by the effect of both CNI drugs. Measuring the levels of PAI-1 in blood and urine of kidney transplant patients has not proved useful for detecting CNI induced nephrotoxicity. However, we found that the appearance of Fascin-1 in urine of kidney and lung transplanted patients could be indicating early renal dysfunction caused by CNIs. Moreover, we found Fascin-1 in urinary exosomes from kidney transplanted patients. This fact helps explaining why a cytoskeleton derived protein appears in the extracellular medium. The obtained results suggest that the release into the environment of Fascin-1 induced by CNIs is dependent on the activation of Protein kinase C

Identificació de biomarcadors precoços de nefrotoxicitat induïda per fàrmacs anticalcineurínics

El transplantament renal ha suposat una millora significativa de la qualitat de vida dels pacients amb dany renal crònic. Tot i això, l'empelt acaba perdent funcionalitat i es desenvolupa una patologia anomenada nefropatia crònica de l'empelt (CAN). Les causes d'aquesta patologia poden ser el rebuig immunològic de l'empelt renal o d'altres lesions com les causades per la isquèmia-reperfusió pròpies del procés quirúrgic o les degudes al propi tractament immunosupressor amb fàrmacs anticalcineuríncs (CNIs), Ciclosporina A (CsA) o FK-506. Els mètodes de mesura de la funció renal tradicionals com ara els nivells de creatinina en sèrum i la taxa de filtració glomerular, no permeten fer un diagnòstic de disfunció renal a l'inici i precís que permeti distingir el dany causat per factors immunològics dels no immunològics, com per exemple la nefrotoxicitat per fàrmacs CNIs. Per aquest motiu, l'objectiu d'aquesta tesi és la identificació de proteïnes diferencialment secretades per cèl·lules tubulars humanes en cultiu sotmeses a diferents noxes en condicions subtòxiques (CsA, FK506, Rapamicina i Staurosporina). La hipòtesi de treball és que, potencialment, aquestes proteïnes podrien ser detectades en sang i orina de pacient trasplantats i ser útils com a biomarcadors primerencs específics de la nefrotoxicitat causada per fàrmacs CNIs. S'han obtingut mapes proteòmics de les proteïnes secretades (secretomes) en cada condició subtòxica i s'han determinat les proteïnes diferencialment secretades en cada cas. Entre les proteïnes específicament secretades per CsA i/o FK-506 hem analitzat la vàlua de dues d'elles com a biomarcador de dany renal per CNIs: Plasminogen activator-inhibitor-1 (PAI-1), diferencialment secretada per CsA, i Fascina-1, secretada per efecte d'ambdós fàrmacs CNIs. La mesura dels nivells de PAI-1 en sang i orina de pacients trasplantats de ronyó no ha resultat ser útil per detectar dany renal per fàrmacs CNIs. En canvi, hem observat que l'aparició de Fascina-1 en orina de pacients trasplantats de ronyó i de pulmó sembla indicar disfunció renal precoç produïda per fàrmacs CNIs. També, hem detectat Fascina-1 en exosomes urinaris de pacients trasplantats de ronyó fet que permet explicar l'aparició d'una proteïna dels citoesquelet al medi extracel·lular. Els resultats obtinguts suggereixen que l'alliberació al medi de Fascina-1 induïda per fàrmacs CNIs és depenent de l'activació de la proteïna quinasa C.Renal transplantation has led to a significant improvement in the quality of life of patients with chronic kidney disease. However, over the years the graft loses functionality and develops a pathology called Chronic Allograft Nephropathy (CAN). The causes of this condition can be immune rejection of the graft or other injuries such as those caused by ischemia-reperfusion resulting from the surgical procedure itself or due to the Calcineurin Inhibitor (CNI) immunosuppressive treatment with Cyclosporine A (CsA) or FK-506. The traditional methods of measurement of renal function such as serum levels of creatinine and glomerular filtration rate, do not allow a diagnosis of renal dysfunction at the beginning and accurate enough to distinguish between the damage caused by immunological and non immunological factors such as CNI induced nephrotoxicity. For this reason, the aim of this thesis is the identification of proteins differentially secreted by human tubular cells in culture under different noxious treatments (CsA, FK506, Rapamycin and Staurosporine) at sublethal conditions. The working hypothesis is that, potentially, these proteins could be detected in blood or urine of transplanted patients and be useful as specific biomarkers of early nephrotoxicity caused by CNIs. Proteomic maps were obtained of secreted proteins (secretome) in each sublethal condition and differentially secreted proteins were determined in each case. Among the proteins specifically secreted by CsA and/or FK-506 we have analyzed the value of two of them as a biomarker of CNI induced kidney damage: Plasminogen activator inhibitor-1 (PAI-1), differentially secreted by CsA, and Fascin-1, secreted by the effect of both CNI drugs. Measuring the levels of PAI-1 in blood and urine of kidney transplant patients has not proved useful for detecting CNI induced nephrotoxicity. However, we found that the appearance of Fascin-1 in urine of kidney and lung transplanted patients could be indicating early renal dysfunction caused by CNIs. Moreover, we found Fascin-1 in urinary exosomes from kidney transplanted patients. This fact helps explaining why a cytoskeleton derived protein appears in the extracellular medium. The obtained results suggest that the release into the environment of Fascin-1 induced by CNIs is dependent on the activation of Protein kinase C

The New Era for Reno-Cardiovascular Treatment in Type 2 Diabetes

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease in the developed world. Until 2016, the only treatment that was clearly demonstrated to delay the DKD was the renin-angiotensin system blockade, either by angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. However, this strategy only partially covered the DKD progression. Thus, new strategies for reno-cardiovascular protection in type 2 diabetic patients are urgently needed. In the last few years, hypoglycaemic drugs, such as sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists, demonstrated a cardioprotective effect, mainly in terms of decreasing hospitalization for heart failure and cardiovascular death in type 2 diabetic patients. In addition, these drugs also demonstrated a clear renoprotective effect by delaying DKD progression and decreasing albuminuria. Another hypoglycaemic drug class, dipeptidyl peptidase 4 inhibitors, has been approved for its use in patients with advanced chronic kidney disease, avoiding, in part, the need for insulinization in this group of DKD patients. Studies in diabetic and non-diabetic experimental models suggest that these drugs may exert their reno-cardiovascular protective effect by glucose and non-glucose dependent mechanisms. This review focuses on newly demonstrated strategies that have shown reno-cardiovascular benefits in type 2 diabetes and that may change diabetes management algorithm

Matrix Metalloproteinases in Diabetic Kidney Disease

Around the world diabetic kidney disease (DKD) is the main cause of chronic kidney disease (CKD), which is characterized by mesangial expansion, glomerulosclerosis, tubular atrophy, and interstitial fibrosis. The hallmark of the pathogenesis of DKD is an increased extracellular matrix (ECM) accumulation causing thickening of the glomerular and tubular basement membranes, mesangial expansion, sclerosis, and tubulointerstitial fibrosis. The matrix metalloproteases (MMPs) family are composed of zinc-dependent enzymes involved in the degradation and hydrolysis of ECM components. Several MMPs are expressed in the kidney; nephron compartments, vasculature and connective tissue. Given their important role in DKD, several studies have been performed in patients with DKD proposing that the measurement of their activity in serum or in urine may become in the future markers of early DKD. Studies from diabetic nephropathy experimental models suggest that a balance between MMPs levels and their inhibitors is needed to maintain renal homeostasis. This review focuses in the importance of the MMPs within the kidney and their modifications at the circulation, kidney and urine in patients with DKD. We also cover the most important studies performed in experimental models of diabetes in terms of MMPs levels, renal expression and its down-regulation effec

Endothelin Receptor Antagonists in Kidney Disease

Endothelin (ET) is found to be increased in kidney disease secondary to hyperglycaemia, hypertension, acidosis, and the presence of insulin or proinflammatory cytokines. In this context, ET, via the endothelin receptor type A (ETA) activation, causes sustained vasoconstriction of the afferent arterioles that produces deleterious effects such as hyperfiltration, podocyte damage, proteinuria and, eventually, GFR decline. Therefore, endothelin receptor antagonists (ERAs) have been proposed as a therapeutic strategy to reduce proteinuria and slow the progression of kidney disease. Preclinical and clinical evidence has revealed that the administration of ERAs reduces kidney fibrosis, inflammation and proteinuria. Currently, the efficacy of many ERAs to treat kidney disease is being tested in randomized controlled trials; however, some of these, such as avosentan and atrasentan, were not commercialized due to the adverse events related to their use. Therefore, to take advantage of the protective properties of the ERAs, the use of ETA receptor-specific antagonists and/or combining them with sodium-glucose cotransporter 2 inhibitors (SGLT2i) has been proposed to prevent oedemas, the main ERAs-related deleterious effect. The use of a dual angiotensin-II type 1/endothelin receptor blocker (sparsentan) is also being evaluated to treat kidney disease. Here, we reviewed the main ERAs developed and the preclinical and clinical evidence of their kidney-protective effects. Additionally, we provided an overview of new strategies that have been proposed to integrate ERAs in kidney disease treatment

Matrix metalloproteinases in diabetic kidney disease

Around the world diabetic kidney disease (DKD) is the main cause of chronic kidney disease (CKD), which is characterized by mesangial expansion, glomerulosclerosis, tubular atrophy, and interstitial fibrosis. The hallmark of the pathogenesis of DKD is an increased extracellular matrix (ECM) accumulation causing thickening of the glomerular and tubular basement membranes, mesangial expansion, sclerosis, and tubulointerstitial fibrosis. The matrix metalloproteases (MMPs) family are composed of zinc-dependent enzymes involved in the degradation and hydrolysis of ECM components. Several MMPs are expressed in the kidney; nephron compartments, vasculature and connective tissue. Given their important role in DKD, several studies have been performed in patients with DKD proposing that the measurement of their activity in serum or in urine may become in the future markers of early DKD. Studies from diabetic nephropathy experimental models suggest that a balance between MMPs levels and their inhibitors is needed to maintain renal homeostasis. This review focuses in the importance of the MMPs within the kidney and their modifications at the circulation, kidney and urine in patients with DKD. We also cover the most important studies performed in experimental models of diabetes in terms of MMPs levels, renal expression and its down-regulation effec