Endocrinological disorders in acute kidney injury: an often overlooked field of clinical research.

Acute kidney injury (AKI) is a common comorbidity, affecting approximately one in five hospitalized adults. The kidney is the site for the production, metabolism or excretion of most hormones, including the production of erythropoietin (EPO), the active form of vitamin D, renin, thrombopoietin, and the excretion of insulin, catecholamines, gastrin and many other hormones. Therefore, it is reasonable to say that AKI can have a considerable impact on the endocrine system. Although the effects of AKI on various parameters, including cardiovascular parameters, serum electrolytes and acid-base disorders, neuro-humoral mechanisms and neurological outcomes have been extensively studied, the endocrinological consequences of AKI are understudied. Thyroid dysfunction, mainly euthyroid sick syndrome, hypo/hyperglycemia, bone mineral disorders, changes in EPO and atrial natriuretic peptide (ANP) levels are commonly found in AKI. EPO, thyroxine and ANP administration have been evaluated as potential tools to prevent or treat AKI with varying success, while the effects of AKI on some key hormones, including cortisol and insulin, have never been studied. Aim of this narrative review is to illustrate what is known and what is not known about the endocrinological outcomes of AKI. Few clinical trials are ongoing: however, there is a clear need for large-scale randomized controlled trials investigating the endocrinological consequences of AKI.

Sodium-glucose cotransporter inhibition in polycystic kidney disease: fact or fiction.

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent hereditary kidney disease. Recent evidence suggests that the pathogenesis of ADPKD is a complex web of abnormal cellular processes including altered cell signaling, disordered cell metabolism, impaired autophagy, increased apoptosis, mitochondrial dysfunction and chronic inflammation. Sodium-glucose cotransporter (SGLT) inhibitors (SGLTi) reduce body weight, blood pressure and blood glucose levels, have kidney and cardiovascular protective activity, and have been reported to decrease inflammation, increase autophagy and improve mitochondrial dysfunction. We now review results from preclinical studies on SGLTi for ADPKD identified through a systematic search of the MEDLINE, Cochrane Library, Embase and PubMed databases. Potential underlying mechanisms for the conflicting results reported as well as implications for clinical translation are discussed, as ADPKD patients were excluded from clinical trials exploring kidney protection by SGLT2 inhibitors (SGLT2i). However, they were not excluded from cardiovascular safety trials or trials for cardiovascular conditions. A post-hoc analysis of the kidney function trajectories and safety of SGLT2i in ADPKD patients enrolled in such trials may provide additional information. In conclusion, SGLT2i are cardio- and nephroprotective in diverse clinical situations. Currently, it is unclear whether ADPKD patients may benefit from SGLT2i in terms of kidney function preservation, and their safety in this population remains unexplored. We propose a roadmap to address this unmet clinical need.

Uric acid in metabolic syndrome: Does uric acid have a definitive role?

Increased serum uric acid (SUA) levels are commonly seen in patients with metabolic syndrome and are widely accepted as risk factors for hypertension, gout, non-alcoholic fatty liver disease, chronic kidney disease (CKD), and cardiovascular diseases. Although some ambiguity for the exact role of uric acid (UA) in these diseases is still present, several pathophysiological mechanisms have been identified such as increased oxidative stress, inflammation, and apoptosis. Accumulating evidence in genomics enlightens genetic variabilities and some epigenetic changes that can contribute to hyperuricemia. Here we discuss the role of UA within metabolism and the consequences of asymptomatic hyperuricemia while providing newfound evidence for the associations between UA and gut microbiota and vitamin D. Increased SUA levels and beneficial effects of lowering SUA levels need to be elucidated more to understand its complicated function within different metabolic pathways and set optimal target levels for SUA for reducing risks for metabolic and cardiovascular diseases.

The Use of Healthy Eating Index 2015 and Healthy Beverage Index for Predicting and Modifying Cardiovascular and Renal Outcomes.

PURPOSE OF REVIEW: With the wide recognition of the importance of dietary patterns rather than isolated nutrient groups on health outcomes, numerous diet quality indices have been designed to evaluate the overall food intake quality in the last two decades. RECENT FINDINGS: The newest version of the Healthy Eating Index (HEI), HEI-2015, is a diet quality index that measures adherence to the recommendations of the 2015-2020 Dietary Guidelines for Americans. While the key nutrient groups are included in most diet quality indices, differences in other components and the scoring system differentiate HEI. The Healthy Beverage Index (HBI) was recently introduced. Previous literature has confirmed the association of the older versions of HEI with metabolic syndrome, inflammatory markers, and negative health outcomes including cardiovascular disease, type 2 diabetes mellitus, chronic kidney disease, and all-cause mortality. This review presents the existing evidence on the association of HEI-2015 and HBI with health markers and long-term outcome, provides guidance on their use, and identifies persisting challenges such as the development of simple, unified, and objective tools to characterize healthy diets in routine clinical practice.

Cardiorenal Metabolic Consequences of Nighttime Snacking: Is it an Innocent Eating Behavior?

PURPOSE OF REVIEW: Health consequences of nighttime eating, as a publicly discussed eating behavior type, have been speculated lately. Nighttime eating has been linked to various metabolic outcomes including hyperlipidemia, hypertriglyceridemia, hyperglycemia, weight gain, elevated blood pressure, obesity, and metabolic syndrome, and cardiorenal outcomes such as atherosclerosis, a decline in eGFR, and proteinuria. RECENT FINDINGS: Although the exact underlying pathophysiological mechanism is not yet clear, multiple hypotheses including disrupted circadian rhythm, altered hormonal levels, and decline in cellular regeneration have been proposed. In this review, we aim to evaluate the growing literature on nighttime eating behavior in terms of metabolic and cardiorenal outcomes, pathophysiological basis, and potential therapeutic alternatives.

Long-term effect of COVID-19 infection on hemodialysis patients: Should we follow hemodialysis patients more closely?

During the coronavirus disease 2019 (COVID-19) pandemic, hemodialysis patients constitute one of the most vulnerable patient populations as they have more significant comorbidities and need to visit healthcare settings frequently even under pandemic conditions. It was also largely demonstrated that hemodialysis patients have high mortality rates with severe to fatal disease due to COVID-19 during their initial hospitalization. Even though the functional decline and fatigue after severe infections are not a novel entity, some long-term effects of COVID-19 have drawn attention with their prolonged effects even after discharge. A recent prospective, observational study by Carriazo et al. provided the first evidence to compare long-term mortality rates of hemodialysis patients with and without COVID-19. Carriazo et al. stated a hazard ratio of 3.00 for the mortality rates of hemodialysis patients over a 1-year follow-up period after their COVID-19 diagnosis. They emphasized that the high mortality rates of hemodialysis patients with COVID-19 are not limited to the initial hospitalization period but also continue after discharge, especially in the first 3 months. In light of this study, it can be recommended that hemodialysis patients with COVID-19 should be monitored closely and continuously, and hemodialysis patients should be prioritized for vaccination against COVID-19 with close follow-up for their antibody levels.

The assessment of hypertension in kidney transplant patients: time to change our approach?

Kidney transplantation (KT) is an increasingly utilized treatment for end-stage kidney disease. Hypertension either as a cause of kidney disease or as a complication of chronic kidney disease is the most frequently encountered comorbidity of KT patients. Hence, the management of hypertension in KT patients is crucial to prolong patient and graft survival. Ambulatory blood pressure monitoring (ABPM) appeared as a promising technique that has superiority over office and home blood pressure (BP) monitoring to correctly diagnose and manage hypertension. A recent meta-analysis by Pisano et al. including 42 studies with 4115 participants provided strong data for the comparison of ABPM with office BP monitoring in KT patients. In addition to the current literature knowledge, the findings of Pisano et al. filled the long-awaited evidence gap to suggest ABPM as a first-line BP monitoring technique for KT patients. Despite its disadvantages, such as patient discomfort, cost-effectiveness and limited availability, ABPM has crucial advantages in the management of hypertension including the detection of abnormal circadian BP patterns, the assessment of effects of physical activity and short-term variability of BP, and the exclusion of masked and white-coat hypertension.

Fatty kidney: A possible future for chronic kidney disease research.

BACKGROUND: Metabolic syndrome is a growing twenty-first century pandemic associated with multiple clinical comorbidities ranging from cardiovascular diseases, non-alcoholic fatty liver disease and polycystic ovary syndrome to kidney dysfunction. A novel area of research investigates the concept of fatty kidney in the pathogenesis of chronic kidney disease, especially in patients with diabetes mellitus or metabolic syndrome. AIM: To review the most updated literature on fatty kidney and provide future research, diagnostic and therapeutic perspectives on a disease increasingly affecting the contemporary world. MATERIALS AND METHOD: We performed an extensive literature search through three databases including Embase (Elsevier) and the Cochrane Central Register of Controlled Trials (Wiley) and PubMed/Medline Web of Science in November 2021 by using the following terms and their combinations: 'fatty kidney', 'ectopic fat', 'chronic kidney disease', 'cardiovascular event', 'cardio-metabolic risk', 'albuminuria' and 'metabolic syndrome'. Each study has been individually assessed by the authors. RESULTS: Oxidative stress and inflammation, Klotho deficiency, endoplasmic reticulum stress, mitochondrial dysfunction and disruption of cellular energy balance appear to be the main pathophysiological mechanisms leading to tissue damage following fat accumulation. Despite the lack of large-scale comprehensive studies in this novel field of research, current clinical trials demonstrate fatty kidney as an independent risk factor for the development of chronic kidney disease and cardiovascular events. CONCLUSION: The requirement for future studies investigating the pathophysiology, clinical outcomes and therapeutics of fatty kidney is clear.

The Role of Uric Acid in the Acute Myocardial Infarction: A Narrative Review.

Increased serum uric acid (SUA) levels have been associated with various pathologic processes such as increased oxidative stress, inflammation, and endothelial dysfunction. Thus, it is not surprising that increased SUA is associated with various adverse outcomes including cardiovascular (CV) diseases. Recent epidemiological evidence suggests that increased SUA may be related to acute myocardial infarction (AMI). Accumulating data also showed that elevated UA has pathophysiological role in the development of AMI. However, there are also studies showing that SUA is not related to the risk of AMI. In this narrative review, we summarized the recent literature data regarding SUA and AMI after providing some background information for the association between UA and coronary artery disease. Future studies will show whether decreasing SUA levels is beneficial for outcomes related to AMI and the optimum SUA levels for best outcomes in CV diseases.

Effect of sodium-glucose cotransporter 2 inhibitors on hemoglobin and hematocrit levels in type 2 diabetes: a systematic review and meta-analysis.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve outcomes of patients with type 2 diabetes at high cardiovascular risk and chronic kidney disease. Recent studies showed an increase in hemoglobin and hematocrit after SGLT2i treatment. MATERIALS AND METHODS: We did a systematic review and meta-analysis of randomized, double-blind, placebo-controlled studies of SGLT2i in patients with type 2 diabetes. We searched through PubMed/Medline, Web of Science, Embase (Elsevier), and the Cochrane Central Register of Controlled Trials (Wiley) from January 2010 to January 2021. RESULTS: We included seventeen randomized, double-blind, placebo-controlled studies. The total number of evaluated patients was 14,748. The treatment arm consisted of canagliflozin, dapagliflozin, empagliflozin and ipragliflozin. SGLT2i therapy significantly increased hemoglobin levels when compared to placebo (MD 5.60 g/L, 95% CI 3.73-7.47 g/L, P < 0.00001, considerable heterogeneity-I2 = 94%). Each SGLT2i also led to a significant increase in the hematocrit level when compared to placebo (MD 1.32%, 95% CI 1.21-1.44, P < 0.00001, considerable heterogeneity-I2 = 99%). CONCLUSIONS: SGLT2i led to significant increases in hemoglobin and hematocrit levels when compared to placebo. In addition to their cardiovascular effect, SGLT2i also increases hemoglobin and hematocrit levels.

Substitution of Sugar-Sweetened Beverages for Other Beverages: Can It Be the Next Step Towards Healthy Aging?

PURPOSE OF REVIEW: With the prolongation of life expectancy, the gap between lifespan and "health span," the disease-free lifespan, has been widening due to the massive burden of age-related chronic diseases and research on healthy aging has been gaining momentum. A growing body of evidence suggests that diet is a strong determinant of healthy aging and consumption of sugar-sweetened beverages (SSB), a major source of added sugars, predicts poor health outcomes in the aging population, including cardiovascular disease, diabetes, and cancer. Evidence further supports a link between sugar-sweetened beverages-triggered pathological processes and biologic factors of aging, including inflammaging, oxidative stress, and alterations in intestinal microbiota. At present, substitution of sugar-sweetened beverages with healthier alternative beverage remains the most robust strategy to limit the deleterious effects of sugar-sweetened beverages on health worldwide and may help achieve healthy longevity. The purpose of this review is to provide an overview of mechanisms by which sugar-sweetened beverages consumption may impact the physiological aging process and how a simple intervention of beverage replacement may promote healthy aging. RECENT FINDINGS: Recent findings indicate that SSB are associated with accelerated aging phenotype and activate various adverse biological processes such as chronic inflammation, oxidative stress, insulin resistance, and gut dysbiosis. Replacing SSB with healthier beverages may be a reasonable option to reduce the burden of chronic disease in the aging population and even prolong life and healthspan.

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.

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.

Virulence Determinants of Colistin-Resistant K. pneumoniae High-Risk Clones.

We proposed the hypothesis that high-risk clones of colistin-resistant K. pneumoniae (ColR-Kp) possesses a high number of virulence factors and has enhanced survival capacity against the neutrophil activity. We studied virulence genes of ColR-Kp isolates and neutrophil response in 142 patients with invasive ColR-Kp infections. The ST101 and ST395 ColR-Kp infections had higher 30-day mortality (58%, p = 0.005 and 75%, p = 0.003). The presence of yersiniabactin biosynthesis gene (ybtS) and ferric uptake operon associated gene (kfu) were significantly higher in ST101 (99%, p ≤ 0.001) and ST395 (94%, p < 0.012). Being in ICU (OR: 7.9; CI: 1.43-55.98; p = 0.024), kfu (OR:27.0; CI: 5.67-179.65; p < 0.001) and ST101 (OR: 17.2; CI: 2.45-350.40; p = 0.01) were found to be predictors of 30-day mortality. Even the neutrophil uptake of kfu+-ybtS+ ColR-Kp was significantly higher than kfu--ybtS- ColR-Kp (phagocytosis rate: 78% vs. 65%, p < 0.001), and the kfu+-ybtS+ ColR-Kp survived more than kfu--ybtS- ColR-Kp (median survival index: 7.90 vs. 4.22; p = 0.001). The kfu+-ybtS+ ColR-Kp stimulated excessive NET formation. Iron uptake systems in high-risk clones of colistin-resistant K. pneumoniae enhance the success of survival against the neutrophil phagocytic defense and stimulate excessive NET formation. The drugs targeted to iron uptake systems would be a promising approach for the treatment of colistin-resistant high-risk clones of K. pneumoniae infections.

Sodium and ultrafiltration profiling in hemodialysis: A long-forgotten issue revisited.

Sodium and ultrafiltration profiling are method of dialysis in which dialysate sodium concentration and ultrafiltration rate are altered during the course of the dialysis session. Sodium and ultrafiltration profiling have been used, commonly simultaneously, to improve hemodynamic stability during hemodialysis. Sodium profiling is particularly effective in decreasing the incidence of intradialytic hypotension, while ultrafiltration profiling is suggested to decrease subclinical repeated end organ ischemia during dialysis. However, complications such as increased interdialytic weight gain and thirst due to sodium excess have prevented widespread use of sodium profiling. Evidence suggest that different sodium profiling techniques may lead to different clinical results, and preferring sodium balance neutral sodium profiling may mitigate adverse effects related to sodium overload. However, evidence is lacking on the long-term clinical outcomes of different sodium profiling methods. Optimal method of sodium profiling as well as the utility of sodium/ultrafiltration profiling in routine practice await further clinical investigation.

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.

Role of Klotho in the Development of Essential Hypertension.

Klotho has antiaging properties, and serum levels decrease with physiological aging and aging-related diseases, such as hypertension, cardiovascular, and chronic kidney disease. Klotho deficiency in mice results in accelerated aging and cardiovascular injury, whereas Klotho supplementation slows down the progression of aging-related diseases. The pleiotropic functions of Klotho include, but are not limited to, inhibition of insulin/IGF-1 (insulin-like growth factor 1) and WNT (wingless-related integration site) signaling pathways, suppression of oxidative stress and aldosterone secretion, regulation of calcium-phosphate homeostasis, and modulation of autophagy with inhibition of apoptosis, fibrosis, and cell senescence. Accumulating evidence shows an interconnection between Klotho deficiency and hypertension, and Klotho gene polymorphisms are associated with hypertension in humans. In this review, we critically review the current understanding of the role of Klotho in the development of essential hypertension and the most important underlying pathways involved, such as the FGF23 (fibroblast growth factor 23)/Klotho axis, aldosterone, Wnt5a/RhoA, and SIRT1 (Sirtuin1). Based on this critical review, we suggest avenues for further research.