Renin angiotensin system-induced muscle wasting: putative mechanisms and implications for clinicians.

Renin angiotensin system (RAS) alters various mechanisms related to muscle wasting. The RAS system consists of classical and non-classical pathways, which mostly function differently. Classical RAS pathway, operates through angiotensin II (AngII) and angiotensin type 1 receptors, is associated with muscle wasting and sarcopenia. On the other hand, the non-classical RAS pathway, which operates through angiotensin 1-7 and Mas receptor, is protective against sarcopenia. The classical RAS pathway might induce muscle wasting by variety of mechanisms. AngII reduces body weight, via reduction in food intake, possibly by decreasing hypothalamic expression of orexin and neuropeptide Y, insulin like growth factor-1 (IGF-1) and mammalian target of rapamycin (mTOR), signaling, AngII increases skeletal muscle proteolysis by forkhead box transcription factors (FOXO), caspase activation and muscle RING-finger protein-1 transcription. Furthermore, AngII infusion in skeletal muscle reduces phospho-Bad (Ser136) expression and induces apoptosis through increased cytochrome c release and DNA fragmentation. Additionally, Renin angiotensin system activation through AT1R and AngII stimulates tumor necrosis factor-α, and interleukin-6 which induces muscle wasting, Last but not least classical RAS pathway, induce oxidative stress, disturb mitochondrial energy metabolism, and muscle satellite cells which all lead to muscle wasting and decrease muscle regeneration. On the contrary, the non-classical RAS pathway functions oppositely to mitigate these mechanisms and protects against muscle wasting. In this review, we summarize the mechanisms of RAS-induced muscle wasting and putative implications for clinical practice. We also emphasize the areas of uncertainties and suggest potential research areas.

Hypersensitive Reactions During Hemodialysis Treatment: What Do We Need to Know?

Kidney replacement therapies (KRTs) including hemodialysis (HD) are one of the treatment options for most of the patients with end-stage kidney disease. Although HD is vital for these patients, it is not hundred percent physiological, and various adverse events including hypersensitivity reactions may occur. Fortunately, these reactions are rare in total and less when compared to previous decades, but it is still very important for at least two reasons: First, the number of patients receiving kidney replacement treatment is increasing globally; and the cumulative number of these reactions may be substantial. Second, although most of these reactions are mild, some of them may be very severe and even lead to mortality. Thus, it is very important to have basic knowledge and skills to diagnose and treat these reactions. Hypersensitivity reactions can occur at any component of dialysis machinery (access, extracorporeal circuit, medications, etc.). The most important preventive measure is to avoid the allergen. However, even with very specific test, sometimes the allergen cannot be found. In mild conditions, HD can be contained with non-specific treatment (topical creams, antihistaminics, corticosteroids). In more severe conditions, treatment must be stopped immediately, blood should not be returned to patient, drugs must be stopped, and rules of general emergency treatment must be followed.

The role of glycosaminoglycans in blood pressure regulation.

Essential hypertension (HT) is the global health problem and is a major risk factor for the development of cardiovascular and kidney disease. High salt intake has been associated with HT and impaired kidney sodium excretion is considered to be a major mechanism for the development of HT. Although kidney has a very important role in regulation of BP, this traditional view of BP regulation was challenged by recent findings suggesting that nonosmotic tissue sodium deposition is very important for BP regulation. This new paradigm indicates that sodium can be stored and deposited nonosmotically in the interstitium without water retention and without increased BP. One of the major determinants of this deposition is glycosaminoglycans (GAGs). By binding to GAGs found in the endothelial surface layer (ESL) which contains glycocalyx, sodium is osmotically inactivated and not induce concurrent water retention. Thus, GAGs has important function for homeostatic BP and sodium regulation. In the current review, we summarized the role of GAGs in ESL and BP regulation.

Hypertension and cellular senescence.

Essential or primary hypertension is a wordwide health problem. Elevated blood pressure (BP) is closely associated not only with increased chronological aging but also with biological aging. There are various common pathways that play a role in cellular aging and BP regulation. These include but not limited to inflammation, oxidative stress, mitochondrial dysfunction, air pollution, decreased klotho activity increased renin angiotensin system activation, gut dysbiosis etc. It has already been shown that some anti-hypertensive drugs have anti-senescent actions and some senolytic drugs have BP lowering effects. In this review, we have summarized the common mechanisms underlying cellular senescence and HT and their relationships. We further reviewed the effect of various antihypertensive medications on cellular senescence and suggest further issues to be studied.

Interconnections of fibroblast growth factor 23 and klotho with erythropoietin and hypoxia-inducible factor.

Bone marrow (BM) hematopoiesis is tightly regulated process and bone components such as osteoblasts, extracellular matrix, and minerals influence hematopoiesis via regulation of hematopoietic stem cell function. Erythropoietin (EPO) secreted mostly by renal EPO producing (REP) cells which employ the hypoxia-inducible factor (HIF) pathway. When tissue hypoxia occurs, HIFs bind to hypoxia response element in the EPO promoter and induce EPO production. EPO binds to the EPO receptor on red cell progenitors in the BM and triggers expansion of red cell mass. Fibroblast growth factor-23 (FGF23) which is secreted mostly by osteoblasts and less by BM impacts hematopoiesis by influencing EPO production. Reciprocally, increases of EPO (acute or chronic) influence both FG23 production and cleavage resulting in variation of c fragment FGF23 (cFGF23) and intact FGF23 (iFGF23) ratios. As HIFs stimulate EPO production, they indirectly affect FGF23. Direct stimulation of FGF23 synthesis by binding of HIF on FGF23 promoter is also suggested. FGF23 cleavage by furin is another potential mechanism affecting FGF23 levels. Klotho is present in membrane-bound (transmembrane) and free (circulating) forms. Transmembrane klotho is the co-receptor of FGF23 and forms complexes with FGF23 receptors in the membrane surface and required for FGF23 actions. Recent evidence showed that klotho is also associated with EPO and HIF production suggesting a complex relationship between FGF23, klotho, EPO, and HIF. In this review, we have summarized the connections between FGF23, klotho, HIF, and EPO and their reflections to hematopoiesis.

Morning blood pressure surge in renal transplant recipients: Its relation to graft function and arterial stiffness.

BACKGROUND: When the blood pressure rises before awakening in the morning, it is called as morning blood pressure pulse (MBPS). MBPS is considered to be an independent risk factor for cardiovascular disease. The aim of this study was to investigate the associations between MBPS, graft function, arterial stiffness and echocardiographic indices in renal transplant recipients. METHODS: Among 600 renal transplant recipients, 122 patients who had a history of hypertension and were taking at least one antihypertensive medication were enrolled in the study. Arterial stiffness was measured by carotid-femoral pulse wave velocity (PWv), and echocardiographic indices were assessed. 24 h ambulatory blood pressure was monitored for all patients. MBPS was calculated by subtracting morning systolic blood pressure from minimal asleep systolic blood pressure. RESULTS: Mean morning, day time and asleep systolic blood pressure values were 171.2 ± 23.9, 137.9 ± 18.1, and 131.7 ± 18.9, respectively. Nondipper hypertension status was observed in 93 patients. Mean MBPS was 35.6 ± 19.5 mm Hg, means PWv was 6.5 ± 2.0 m/s. Patients with MBPS ≥ 35 mm Hg, had significantly lower eGFR and higher proteinuria, PWv. higher left atrium volume and LVMI. In regression analysis, day time systolic blood pressure, asleep systolic blood pressure, morning blood pressure surge, nondipper status and left ventricular mass index were detected as the predictors of graft function. CONCLUSIONS: Increased morning blood pressure surge is associated with graft dysfunction, increased arterial stiffness and LVMI that contribute to cardiovascular mortality and morbidity in renal transplant recipients.

Brain-derived neurotrophic factor (BDNF): a multifaceted marker in chronic kidney disease.

Despite advances in diagnostic tools and therapeutic options, chronic kidney disease (CKD) is still a global health problem associated with increased morbidity and mortality. Insulin resistance, muscle wasting, malnutrition and chronic inflammation are highly prevalent in CKD patients. Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor-related family and with its receptor tropomyosin-related kinase receptor B impacts cell differentiation, synaptic connectivity and plasticity of the brain. BDNF is well studied in various populations especially in the area of neurology and psychiatry. Recently, there is also an acceleration of BDNF research in CKD and accumulating evidence suggests that BDNF may be a potential prognostic marker in CKD patients. Specifically, studies have shown that BDNF is associated with insulin resistance, muscle wasting, depression, oxidative stress and inflammation in CKD patients. However, the data regarding BDNF in CKD is only in its first steps and various issues must be highlighted in upcoming studies. In this review, we have summarized the findings regarding BDNF and its relationship between insulin resistance, muscle wasting, depression, oxidative stress and inflammation in CKD patients. We also mentioned controversies and possible causes for diverse findings and suggest perspectives in the context of BDNF and CKD.

In-depth review: is hepcidin a marker for the heart and the kidney?

Iron is an essential trace element involved in oxidation-reduction reactions, oxygen transport and storage, and energy metabolism. Iron in excess can be toxic for cells, since iron produces reactive oxygen species and is important for survival of pathogenic microbes. There is a fine-tuning in the regulation of serum iron levels, determined by intestinal absorption, macrophage iron recycling, and mobilization of hepatocyte stores versus iron utilization, primarily by erythroid cells in the bone marrow. Hepcidin is the major regulatory hormone of systemic iron homeostasis and is upregulated during inflammation. Hepcidin metabolism is altered in chronic kidney disease. Ferroportin is an iron export protein and mediates iron release into the circulation from duodenal enterocytes, splenic reticuloendothelial macrophages, and hepatocytes. Systemic iron homeostasis is controlled by the hepcidin-ferroportin axis at the sites of iron entry into the circulation. Hepcidin binds to ferroportin, induces its internalization and intracellular degradation, and thus inhibits iron absorption from enterocytes, and iron release from macrophages and hepatocytes. Recent data suggest that hepcidin, by slowing or preventing the mobilization of iron from macrophages, may promote atherosclerosis and may be associated with increased cardiovascular disease risk. This article reviews the current data regarding the molecular and cellular pathways of systemic and autocrine hepcidin production and seeks the answer to the question whether changes in hepcidin translate into clinical outcomes of all-cause and cardiovascular mortality, and cardiovascular and renal end-points.

Deciphering nutritional interventions for podocyte structure and function.

Despite increasing awareness and therapeutic options chronic kidney disease (CKD) is still and important health problem and glomerular diseases constitute and important percentage of CKD. Proteinuria/albuminuria is not just a marker; but it also plays a direct pathogenic role in renal disease progression of CKD. Glomerular filtration barrier (GFB) which consists of fenestrated endothelial cells, fused basal membrane and interdigitating podocyte foot process and filtration slits between foot process is the major barrier for proteinuria/albuminuria. Many glomerular diseases are characterized by disruption of GFB podocytes, foot process and slit diaphragm. Many proteinuric diseases are non-specifically targeted by therapeutic agents such as steroids and calcineurin inhibitors with systemic side effects. Thus, there is unmet need for more efficient and less toxic therapeutic options to treat glomerular diseases. In recent years, modification of dietary intake, has been gained to treat pathologic processes introducing the concept of 'food as a medicine'. The effect of various nutritional products on podocyte function and structure is also trending, especially in recent years. In the current review, we summarized the effect of nutritional interventions on podocyte function and structure.

The effect of energy restriction on development and progression of chronic kidney disease: review of the current evidence.

Energy restriction (ER) has anti-ageing effects and probably protects from a range of chronic diseases including cancer, diabetes and chronic kidney disease (CKD). Specifically, ER has a positive impact on experimental kidney ageing, CKD (diabetic nephropathy, polycystic kidney disease) and acute kidney injury (nephrotoxic, ischaemia-reperfusion injury) through such mechanisms as increased autophagy, mitochondrial biogenesis and DNA repair, and decreased inflammation and oxidative stress. Key molecules contributing to ER-mediated kidney protection include adenosine monophosphate-activated protein kinase, sirtuin-1 and PPAR-γ coactivator 1α. However, CKD is a complex condition, and ER may potentially worsen CKD complications such as protein-energy wasting, bone-mineral disorders and impaired wound healing. ER mimetics are drugs, such as metformin and Na-glucose co-transporter-2 which mimic the action of ER. This review aims to provide comprehensive data regarding the effect of ER on CKD progression and outcomes.

Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors for diabetes after solid organ transplantation.

Post-transplant diabetes mellitus (PTDM) is a common complication of solid organ transplantation and a major cause of increased morbidity and mortality. Additionally, solid organ transplant patients may have pre-existent type 2 diabetes mellitus (T2DM). While insulin is the treatment of choice for hyperglycemia in the first weeks after transplantation, there is no preferred first line agent for long-term management of PTDM or pre-existent T2DM. Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter 2 (SGLT2) inhibitors improve glycemic control, lower body weight, and blood pressure, are recommended after lifestyle and metformin as initial therapy for diabetic patients with cardiovascular or kidney comorbidities regarding their cardiorenal benefits. Furthermore, the mechanisms of action of GLP-1RA may counteract some of the driving forces for PTDM, as calcineurin-induced ß cell toxicity as per preclinical data, and improve obesity. However, their use in the treatment of PTDM is currently limited by a paucity of data. Retrospective observational and small exploratory studies suggest that GLP-1RA effectively improve glycemic control and induce weight loss in patients with PTDM without interacting with commonly used immunosuppressive agents, although randomized-controlled clinical trials are required to confirm their safety and efficacy. In this narrative review, we evaluate the risk factors and pathogenesis of PTDM and compare the potential roles of GLP-1RA and SGLT2 inhibitors in PTDM prevention and management as well as in pre-existent T2DM, and providing a roadmap for evidence generation on newer antidiabetic drugs for solid organ transplantation.

Sodium-glucose cotransporter 2 inhibitors for diabetes mellitus control after kidney transplantation: Review of the current evidence.

Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) are promising drugs to treat chronic kidney disease patients with or without diabetes mellitus (DM). Besides improving glycemic control, SGLT2i are cardioprotective and kidney protective and decrease bodyweight, serum uric acid, blood pressure, albuminuria and glomerular hyperfiltration. These effects may benefit graft function and survival in kidney transplant (KT) patients. In this review, we evaluate data on the efficacy and safety of SGLT2i for KT patients with DM. Eleven studies with 214 diabetic KT patients treated with SGLT2i have been reported. SGLT2i lowered haemoglobin A1c and bodyweight. While glomerular filtration rate may be reduced in the short-term, it remained similar to baseline after 3-12 months. In two studies, blood pressure decreased and remained unchanged in the others. There were no significant changes in urine protein to creatinine ratio. Regarding safety, 23 patients had urinary tract infections, 2 patients had a genital yeast infection, one had acute kidney injury, and one had mild hypoglycaemia. No cases of ketoacidosis or acute rejection were reported. In conclusion, the limited experience so far suggests that SGLT2i are safe in KT patients with DM, decrease bodyweight and improve glycemic control. However, some of the benefits observed in larger studies in the non-KT population have yet to be demonstrated in KT recipients, including preservation of kidney function, reduction in blood pressure and decreased proteinuria.

Effect of Coffee Consumption on Renal Outcome: A Systematic Review and Meta-Analysis of Clinical Studies.

OBJECTIVE: Drinking coffee is one of the most common daily habits, especially in the developed world. Along with caffeine, coffee has various ingredients that have been suggested to have beneficial effects, including antioxidant, antiinflammatory, anticarcinogenic, antithrombotic and antifibrotic effects. In this systematic review and meta-analysis, we investigated the relationship between coffee intake and chronic kidney disease (CKD) related outcomes. DESIGN AND METHODS: Literature search was performed through PubMed/Medline, Web of Science, Embase (Elsevier), and the Cochrane Central Register of Controlled Trials (Wiley) from 1960 to February 2020. Incidence of CKD, the progression of CKD, and CKD-associated mortality have been evaluated in relation to coffee consumption and the amount of consumption. The Newcastle-Ottawa scale was used for quality assessment of included studies. RESULTS: 12 studies were included in the analysis (7 prospective, 5 cross-sectional) involving 505,841 subjects. 7 studies investigated the relationship between coffee consumption and incident CKD and showed that coffee consumption was associated with a significant decrease in the risk for incident CKD outcome (RR 0.86, 95% CI 0.76 to 0.97, P = .01) with a greater decrease in individuals taking ≥2 cups/day compared to those who drank ≤1 cup/day. There was a significantly lower risk of incident end stage kidney disease (ESKD) in coffee users (HR 0.82, 95% CI 0.72 to 0.94, P = .005). Coffee consumption was also associated with a lower risk of albuminuria (OR 0.81, 95% CI 0.68 to 0.97, P = .02). Overall, the risk of death related to CKD was lower in coffee users (HR 0.72, 95% CI 0.54 to 0.96, P = .02). CONCLUSION: Coffee intake was dose-dependently associated with lower incident CKD, ESKD, and albuminuria.

Immunogenicity of SARS-CoV-2 mRNA vaccine in dialysis and kidney transplant patients: A systematic review.

Kidney transplant recipients and dialysis patients constitute a risk group for severe COVID-19. They are highly advised to get vaccinated according to the current guidelines. However, data on antibody response, cell responses and protection from events, and factors that might alter this response after a routine full series of vaccination remain incomplete for these populations. The aim of this article was to analyze the antibody responses after a full series of mRNA-based SARS-CoV-2 vaccination in kidney transplantation and dialysis patients and to define the factors that alter seroconversion status in these populations. In this systematic review, 18 studies investigating the antibody response to full vaccination with two doses of COVID-19 mRNA vaccines in hemodialysis, peritoneal dialysis, and kidney transplant patients were included. Kidney transplant and dialysis patients have a lower seroconversion rate after mRNA-based SARS-CoV-2 vaccination than the healthy population: 27.2% for kidney transplantation, 88.5% for dialysis patients while all healthy control in these studies seroconverted. Moreover, anti-S antibody titers were lower in seroconverted kidney transplantation or dialysis patients than in healthy control in all studies that assessed this variable. Older age and dialysis vintage, immunosuppressive or chemotherapy treatment, and lower serum albumin, white blood cell, lymphocyte and hemoglobin counts were associated with lower/no antibody response to vaccination. Dialysis patients and kidney transplant recipients have lower seroconversion rates after a full series of mRNA-based SARS-CoV-2 vaccination than the general population. Several factors are associated with an altered antibody response. A third dose could be considered in this patient group.

The Effect of Urine pH and Urinary Uric Acid Levels on the Development of Contrast Nephropathy.

BACKGROUND: Hyperuricemia may cause acute kidney injury by activating inflammatory, pro-oxidative and vasoconstrictive pathways. In addition, radiocontrast causes an acute uricosuria, potentially leading to crystal formation. We therefore aimed to investigate the effect of urine acidity and urine uric acid level on the development of contrast-induced nephropathy (CIN) in patients undergoing elective coronary angiography. METHODS: We enrolled 175 patients who underwent elective coronary angiography. CIN was defined as a >25% increase in the serum creatinine levels relative to basal values 48-72 h after contrast use. Prior to coronary angiography and 48-72 h later, serum uric acid, urea, creatinine, bicarbonate levels, and spot uric acid to creatinine ratio (UACR) were measured. RESULTS: Of the 175 subjects included, 29 (16.6%) developed CIN. Those who developed CIN had a higher prevalence of diabetes, higher UACR (0.60 vs. 0.44, p = 0.014), higher contrast volume, and lower serum sodium level. With univariate analysis of a logistic regression model, the risk of CIN was found to be associated with diabetes (p = 0.0016, OR = 3.8 [95% CI: 1.7-8.7]), urine UACR (p = 0.0027, OR = 9.6 [95% CI: 2.2-42.2]), serum sodium (p = 0.0079, OR = 0.8 [95% CI: 0.77-0.96]), and contrast volume (p = 0.0385, OR = 1.8 [95% CI: 1.03-3.09]). In a multiple logistic regression model with stepwise method of selection, diabetes (p = 0.0120, OR = 3.2 [95% CI: 1.3-8.1]) and UACR (p = 0.0163, OR = 6.9 [95% CI: 1.4-33.4]) were the 2 risk factors finally identified. CONCLUSIONS: We have demonstrated that higher urine UACR is associated with the development of CIN in patients undergoing elective coronary angiography.

Pathological features of COVID-19 infection from biopsy and autopsy series.

Novel coronavirus disease 2019 (COVID-19) which is caused by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) was first identified in December 2019 in Chinese town Wuhan and considered as a pandemic by World Health Organization. The disease has variety of symptoms including fever, shortness of breath, cough, fatigue, loss of smell and taste and diarrhea. While the majority of cases have mild symptoms, some progress to viral pneumonia, multi-organ failure, or cytokine storm and mortality is mostly caused by hypoxemic respiratory failure. Until now, more than 3.5 million people worldwide were infected and more than 240.000 mortality has been occurred. Thus, there is now evidence the disease may affect variety of organs according to accumulating biopsy and autopsy studies. Such pathological studies have potential role on the understanding of clinical outcomes and in the development of novel targeted therapeutic approaches. Given these aforementioned data, in the current manuscript we have summarized the pathological features of COVID-19 derived from biopsy and autopsy series.

COVID-19 and acute kidney injury.

The Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) started in December 2019 and has affected millions of lives worldwide, while many aspects of the illness are still unknown. Current data show that many hospitalized COVID-19 patients suffer from kidney damage, in the form of proteinuria, hematuria or acute kidney injury (AKI). AKI is especially prevalent among severe and critically ill COVID-19 patients and is a predictor of mortality. The pathophysiology of AKI in COVID-19 is unclear. Early reports of histopathologic examination from autopsied kidney tissue show SARS-CoV-2 viral particles in renal tubular cells and podocytes, suggesting direct viral infection, as well as findings of acute tubular necrosis, while rhabdomyolysis-associated AKI and glomerulopathies may also occur. As of today, only remdesivir has been authorized to treat COVID-19. Ongoing research investigates potential of anti-viral and anti-inflammatory agents along with safety and efficacy of commonly prescribed drugs such as renin-angiotensin-aldosterone system blockers. This review discusses the prevalence of AKI and its association with outcome, while highlighting possible mechanisms of AKI and suggesting organ protective measures to prevent the development of kidney damage.

Renal hyperfiltration defined by high estimated glomerular filtration rate: A risk factor for cardiovascular disease and mortality.

Renal hyperfiltration, defined as an increased glomerular filtration rate above normal values, is associated with early phases of kidney disease in the setting of various conditions such as obesity and diabetes. Although it is recognized that glomerular hyperfiltration, that is, increased filtration per nephron unit (usually studied at low glomerular filtration levels and often referred to as single nephron hyperfiltration), is a risk factor for the progression of chronic kidney disease, the implications of having renal hyperfiltration for cardiovascular disease and mortality risk are incompletely understood. Recent evidence from diverse populations, including healthy individuals and patients with diabetes or established cardiovascular disease, suggests that renal hyperfiltration is associated with a higher risk of cardiovascular disease and all-cause mortality. In this review, we critically summarize the existing studies, discuss possible mechanisms, and describe the remaining gaps in our knowledge regarding the association of renal hyperfiltration with cardiovascular disease and mortality risk.