Sodium-glucose cotransporter inhibitors: beyond glycaemic control

SGLT2; Chronic kidney disease; Diabetic nephropathySGLT2; Malaltia renal crònica; Nefropatia diabèticaSGLT2; Enfermedad renal crónica; Nefropatía diabéticaDiabetes 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.The authors are current recipients of research grants from the FONDO DE INVESTIGACIÓN SANITARIA-FEDER, ISCIII, PI17/00257 and REDINREN, RD16/0009/0030

Urinary angiotensin-converting enzyme 2 and metabolomics in COVID-19-mediated kidney injury

COVID-19; Angiotensin-converting enzyme 2; MetabolomicsCOVID-19; Enzim convertidor d'angiotensina 2; MetabolòmicaCOVID-19; Enzima convertidora de angiotensina 2; MetabolómicaBackground Angiotensin-converting enzyme 2 (ACE2), the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is highly expressed in the kidneys. Beyond serving as a crucial endogenous regulator of the renin–angiotensin system, ACE2 also possess a unique function to facilitate amino acid absorption. Our observational study sought to explore the relationship between urine ACE2 (uACE2) and renal outcomes in coronavirus disease 2019 (COVID-19). Methods In a cohort of 104 patients with COVID-19 without acute kidney injury (AKI), 43 patients with COVID-19-mediated AKI and 36 non-COVID-19 controls, we measured uACE2, urine tumour necrosis factor receptors I and II (uTNF-RI and uTNF-RII) and neutrophil gelatinase-associated lipocalin (uNGAL). We also assessed ACE2 staining in autopsy kidney samples and generated a propensity score–matched subgroup of patients to perform a targeted urine metabolomic study to describe the characteristic signature of COVID-19. Results uACE2 is increased in patients with COVID-19 and further increased in those that developed AKI. After adjusting uACE2 levels for age, sex and previous comorbidities, increased uACE2 was independently associated with a >3-fold higher risk of developing AKI [odds ratio 3.05 (95% confidence interval 1.23‒7.58), P = .017]. Increased uACE2 corresponded to a tubular loss of ACE2 in kidney sections and strongly correlated with uTNF-RI and uTNF-RII. Urine quantitative metabolome analysis revealed an increased excretion of essential amino acids in patients with COVID-19, including leucine, isoleucine, tryptophan and phenylalanine. Additionally, a strong correlation was observed between urine amino acids and uACE2. Conclusions Elevated uACE2 is related to AKI in patients with COVID-19. The loss of tubular ACE2 during SARS-CoV-2 infection demonstrates a potential link between aminoaciduria and proximal tubular injury.This work was supported by the Heart and Stroke Foundation (grant 855632 to G.Y.O.) and the Canada Foundation for Innovation (grant 35456). A.V. is a current recipient of a Fundacion Alfonso Martin Escudero–2020 Research Grant

Antioxidant Roles of SGLT2 Inhibitors in the Kidney

Diabetic kidney disease; Mitochondrial dysfunction; Oxidative stressMalaltia renal diabètica; Disfunció mitocondrial; Estrès oxidatiuEnfermedad renal diabética; Disfunción mitocondrial; Estrés oxidativoThe reduction-oxidation (redox) system consists of the coupling and coordination of various electron gradients that are generated thanks to serial reduction-oxidation enzymatic reactions. These reactions happen in every cell and produce radical oxidants that can be mainly classified into reactive oxygen species (ROS) and reactive nitrogen species (RNS). ROS and RNS modulate cell-signaling pathways and cellular processes fundamental to normal cell function. However, overproduction of oxidative species can lead to oxidative stress (OS) that is pathological. Oxidative stress is a main contributor to diabetic kidney disease (DKD) onset. In the kidney, the proximal tubular cells require a high energy supply to reabsorb proteins, metabolites, ions, and water. In a diabetic milieu, glucose-induced toxicity promotes oxidative stress and mitochondrial dysfunction, impairing tubular function. Increased glucose level in urine and ROS enhance the activity of sodium/glucose co-transporter type 2 (SGLT2), which in turn exacerbates OS. SGLT2 inhibitors have demonstrated clear cardiovascular benefits in DKD which may be in part ascribed to the generation of a beneficial equilibrium between oxidant and antioxidant mechanisms.The authors are current recipients of grants from FONDO DE INVESTIGACIÓN SANITARIA-FEDER, ISCIII (PI17/00257 and RICORS RD21/0005/0016), and Fundació la Marató de TV3 (421/C/2020, 759/U/2020 and 215/C/2021)

A Nephrologist Perspective on Obesity: From Kidney Injury to Clinical Management

Malaltia renal crònica; Obesitat; Trasplantament de ronyóEnfermedad renal crónica; Obesidad; Trasplante de riñónChronic kidney disease; Obesity; Kidney transplantationObesity is one of the epidemics of our era. Its prevalence is higher than 30% in the U.S. and it is estimated to increase by 50% in 2030. Obesity is associated with a higher risk of all-cause mortality and it is known to be a cause of chronic kidney disease (CKD). Typically, obesity-related glomerulopathy (ORG) is ascribed to renal hemodynamic changes that lead to hyperfiltration, albuminuria and, finally, impairment in glomerular filtration rate due to glomerulosclerosis. Though not only hemodynamics are responsible for ORG: adipokines could cause local effects on mesangial and tubular cells and podocytes promoting maladaptive responses to hyperfiltration. Furthermore, hypertension and type 2 diabetes mellitus, two conditions generally associated with obesity, are both amplifiers of obesity injury in the renal parenchyma, as well as complications of overweight. As in the native kidney, obesity is also related to worse outcomes in kidney transplantation. Despite its impact in CKD and cardiovascular morbility and mortality, therapeutic strategies to fight against obesity-related CKD were limited for decades to renin-angiotensin blockade and bariatric surgery for patients who accomplished very restrictive criteria. Last years, different drugs have been approved or are under study for the treatment of obesity. Glucagon-like peptide-1 receptor agonists are promising in obesity-related CKD since they have shown benefits in terms of losing weight in obese patients, as well as preventing the onset of macroalbuminuria and slowing the decline of eGFR in type 2 diabetes. These new families of glucose-lowering drugs are a new frontier to be crossed by nephrologists to stop obesity-related CKD progression

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

Diabetes; Diabetic kidney disease; Dipeptidyl peptidase 4 inhibitorsDiabetis; Nefropatia diabètica; Inhibidors de la dipeptidil peptidasa 4Diabetes; Nefropatía diabética; Inhibidores de la dipeptidil peptidasa 4Diabetic 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 algorithms.The authors are current recipients of research grants from the FONDO DE INVESTIGACIÓN SANITARIA-FEDER, ISCIII, PI17/00257, and REDINREN, RD16/0009/0030

The Impact of Age on Mortality in Chronic Haemodialysis Population with COVID-19

Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Hemodiàlisi; MortalitatCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Hemodiálisis; MortalidadCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Haemodialysis; MortalityAge and chronic kidney disease have been described as mortality risk factors for coronavirus disease 2019 (COVID-19). Currently, an important percentage of patients in haemodialysis are elderly. Herein, we investigated the impact of age on mortality among haemodialysis patients with COVID-19. Data was obtained from the Spanish COVID-19 chronic kidney disease (CKD) Working Group Registry. From 18 March 2020 to 27 August 2020, 930 patients on haemodialysis affected by COVID-19 were included in the Registry. A total of 254 patients were under 65 years old and 676 were 65 years or older (elderly group). Mortality was 25.1% higher (95% CI: 22.2–28.0%) in the elderly as compared to the non-elderly group. Death from COVID-19 was increased 6.2-fold in haemodialysis patients as compared to the mortality in the general population in a similar time frame. In the multivariate Cox regression analysis, age (hazard ratio (HR) 1.59, 95% CI: 1.31–1.93), dyspnea at presentation (HR 1.51, 95% CI: 1.11–2.04), pneumonia (HR 1.74, 95% CI: 1.10–2.73) and admission to hospital (HR 4.00, 95% CI: 1.83–8.70) were identified as independent mortality risk factors in the elderly haemodialysis population. Treatment with glucocorticoids reduced the risk of death (HR 0.68, 95% CI: 0.48–0.96). In conclusion, mortality is dramatically increased in elderly haemodialysis patients with COVID-19. Our results suggest that this high risk population should be prioritized in terms of protection and vaccination.The authors are current recipients of FONDOS DE INVESTIGACIÓN SANITARIA—FEDER (ISCIII) PI17/00257, REDINREN RD16/0009/0030, RD/16/0009/0026, and EIN2020-112338

Endothelin Receptor Antagonists in Kidney Disease

Atrasentan; Endothelin; Kidney diseaseAtrasentan; Endotelina; NefropatíaAtrasentan; Endotelina; NefropatiaEndothelin (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.The authors have funding from Fondo de Investigación Sanitaria-Feder, ISCIII, PI21/01292, RICORS RD21/0005/0031, and Marató TV3 421/C/2020, Marató TV3 759/U/2020, Marató TV3 215/C/2021

How to Assess Diabetic Kidney Disease Progression? From Albuminuria to GFR

Malaltia renal crònica; Diabetis mellitus; Malaltia renal diabèticaEnfermedad renal crónica; Diabetes mellitus; Enfermedad renal diabéticaChronic kidney disease; Diabetes mellitus; Diabetic kidney diseaseDiabetic kidney disease (DKD) is one of the most relevant complications of type 2 diabetes and dramatically increases the cardiovascular risk in these patients. Currently, DKD is severely infra-diagnosed, or its diagnosis is usually made at advanced stages of the disease. During the last decade, new drugs have demonstrated a beneficial effect in terms of cardiovascular and renal protection in type 2 diabetes, supporting the crucial role of an early DKD diagnosis to permit the use of new available therapeutic strategies. Moreover, cardiovascular and renal outcome trials, developed to study these new drugs, are based on diverse cardiovascular and renal simple and composite endpoints, which makes difficult their interpretation and the comparison between them. In this article, DKD diagnosis is reviewed, focusing on albuminuria and the recommendations for glomerular filtration rate measurement. Furthermore, cardiovascular and renal endpoints used in classical and recent cardiovascular outcome trials are assessed in a pragmatic way.The authors are current recipients of research grants from the Fondo de Investigación Sanitaria-Feder—Instituto de Salud Carlos III (PI17/00257) and REDinREN (RD16/0009/0030)

Focal and segmental glomerulosclerosis associated with COVID-19 infection

Glomeruloesclerosi; COVID-19Glomerulosclerosis; COVID-19Glomeruloesclerosis; COVID-1

Safety of Obtaining an Extra Biobank Kidney Biopsy Core

Biobank; Chronic kidney disease; Kidney biopsyBiobanco; Enfermedad renal cronica; Biopsia renalBiobanc; Malaltia renal crònica; Biòpsia de ronyóBackground and objectives: Kidney biopsy (KB) is the “gold standard” for the diagnosis of nephropathies and it is a diagnostic tool that presents a low rate of complications. Nowadays, biobank collections of renal tissue of patients with proven renal pathology are essential for research in nephrology. To provide enough tissue for the biobank collection, it is usually needed to obtain an extra kidney core at the time of kidney biopsy. The objective of our study is to evaluate the complications after KB and to analyze whether obtaining an extra core increases the risk of complications. Material and methods: Prospective observational study of KBs performed at Vall d’Hebron Hospital between 2019 and 2020. All patients who accepted to participate to our research biobank of native kidney biopsies were included to the study. Clinical and laboratory data were reviewed and we studied risk factors associated with complications. Results: A total of 221 patients were included, mean age 56.6 (±16.8) years, 130 (58.8%) were men, creatinine was 2.24 (±1.94) mg/dL, proteinuria 1.56 (0.506–3.590) g/24 h, hemoglobin 12.03 (±2.3) g/dL, INR 0.99 (±0.1), and prothrombin time (PT) 11.86 (±1.2) s. A total of 38 patients (17.2%) presented complications associated with the procedure: 13.1% were minor complications, 11.3% (n = 25) required blood transfusion, 1.4% (n = 3) had severe hematomas, 2.3% (n = 5) required embolization, and 0.5% (n = 1) presented arterio-venous fistula. An increased risk for complication was independently associated with obtaining a single kidney core (vs. 2 and 3 cores) (p = 0.021). Conclusions: KB is an invasive and safe procedure with a low percentage of complications. Obtaining an extra kidney core for research does not increase the risk of complications during the intervention, which remains low in concordance with previously published reports.The authors are current recipients of research grant from Red de Investigación Renal (REDINREN, RD16/0009/0030). (RICORS, RD21/0005/0016)