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BACKGROUND AND AIM: Post-transplant diabetes mellitus (PTDM) is a complex condition arising from various factors including immunosuppressive medications, insulin resistance, impaired insulin secretion, and inflammatory processes. Its impact on patient and graft survival is a significant concern in kidney transplant recipients. PTDM's impact on kidney transplant recipients, including patient and graft survival and cardiovascular mortality, is a significant concern, given conflicting findings in previous studies. This meta-analysis was imperative to not only incorporate emerging evidence but also to delve into cause-specific mortality considerations. We aimed to comprehensively evaluate the association between PTDM and clinical outcomes, including all-cause and cardiovascular mortality, sepsis-related mortality, malignancy-related mortality, and graft loss, in kidney transplant recipients. MATERIALS AND METHODS: PubMed, Ovid/Medline, Web of Science, Scopus, and Cochrane Library databases were screened and studies evaluating the effect of PTDM on all-cause mortality, cardiovascular mortality, sepsis-related mortality, malignancy-related mortality, and overall graft loss in adult kidney transplant recipients were included. RESULTS: 53 studies, encompassing a total of 138,917 patients, to evaluate the association between PTDM and clinical outcomes were included. Our analysis revealed a significant increase in all-cause mortality (RR 1.70, 95% CI 1.53 to 1.89, P<0.001) and cardiovascular mortality (RR 1.86, 95% CI 1.36 to 2.54, P<0.001) among individuals with PTDM. Moreover, PTDM was associated with a higher risk of sepsis-related mortality (RR 1.96, 95% CI 1.51 to 2.54, P<0.001) but showed no significant association with malignancy-related mortality (RR 1.20, 95% CI 0.76 to 1.88). Additionally, PTDM was linked to an increased risk of overall graft failure (RR 1.33, 95% CI 1.16 to 1.54, P<0.001). CONCLUSION: These findings underscore the importance of comprehensive management strategies and the need for research targeting PTDM to improve outcomes in kidney transplant recipients.
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Cardiovascular kidney metabolic (CKM) syndrome represents a complex interplay of cardiovascular disease (CVD), chronic kidney disease (CKD), and metabolic comorbidities, posing a significant public health challenge. Gender exerts a critical influence on CKM syndrome, affecting the disease severity and onset through intricate interactions involving sex hormones and key physiological pathways such as the renin-angiotensin system, oxidative stress, inflammation, vascular disease and insulin resistance. It is widely known that beyond the contribution of traditional risk factors, men and women exhibit significant differences in CKM syndrome and its components, with distinct patterns observed in premenopausal women and postmenopausal women compared to men. Despite women generally experiencing a lower incidence of CVD, their outcomes following cardiovascular events are often worse compared to men. The disparities also extend to the treatment approaches for kidney failure, with a higher prevalence of dialysis among men despite women exhibiting higher rates of CKD. The impact of endogenous sex hormones, the correlations between CKM and its components, as well as the long-term effects of treatment modalities using sex hormones, including hormone replacement therapies and gender-affirming therapies, have drawn attention to this topic. Current research on CKM syndrome is hindered by the scarcity of large-scale studies and insufficient integration of gender-specific considerations into treatment strategies. The underlying mechanisms driving the gender disparities in the pathogenesis of CKM syndrome, including the roles of estrogen, progesterone and testosterone derivatives, remain poorly understood, thus limiting their application in personalized therapeutic interventions. This review synthesizes existing knowledge to clarify the intricate relationship between sex hormones, gender disparities, and the progression of CVD within CKM syndrome. By addressing these knowledge gaps, this study aims to guide future research efforts and promote tailored approaches for effectively managing CKD syndrome.
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Obesity represents a prevalent global health concern with significant implications for various diseases, including chronic kidney disease (CKD). Within this landscape, the phenomenon of metabolically healthy obesity has emerged, challenging traditional notions about the health risks associated with excess weight. While traditional CKD risk factors involve obesity, metabolic syndrome, diabetes, and hypertension, the metabolically healthy obese (MHO) subgroup disrupts these assumptions. Our main objective in this study is to integrate existing literature on CKD in MHO individuals. In this endeavor, we delve into the pathophysiological foundations, the transition between obesity phenotypes and their impact on renal health, examine the implications of their metabolic resilience on mortality within a renal context, and explore potential management strategies specifically designed for MHO individuals. Offering a comprehensive overview of the pathophysiology, we cover various factors contributing to the risk of CKD in the metabolically healthy obese setting, including inflammation, cytokines, hemodynamics, and the renin-angiotensin-aldosterone system, gastrointestinal microbiota, diet, exercise, adipose distribution, and lipotoxicity. Through this synthesis, we aim to provide a comprehensive understanding of the risk of CKD in those classified as MHO.
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Cardiovascular-kidney-metabolic (CKM) syndrome and chronic kidney disease (CKD) are two significant comorbidities affecting a large proportion of the general population with considerable crosstalk. In addition to substantial co-incidence of CKD and CKM syndrome in epidemiological studies, clinical and pre-clinical studies have identified similar pathophysiological pathways leading to both entities. Patients with CKM syndrome are more prone to develop acute kidney injury and CKD, while therapeutic alternatives and their success rates are considerably lower in such patient groups. Nevertheless, the association between CKM syndrome and CKD or ESKD is bidirectional rather than being a cause-effect relationship as patients with CKD are also prone to develop peripheral insulin resistance, high blood pressure, and dyslipidemia. Furthermore, such patients are less likely to receive kidney transplantation in addition to the higher allograft dysfunction risk. We hereby aim to evaluate the association in-between kidney diseases and CKM syndrome, including epidemiological data, pre-clinical studies with pathophysiological pathways, and potential therapeutic perspectives.
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Background: The increasing adoption of immune checkpoint inhibitors (ICIs) in clinical settings highlights their efficacy in treating diverse conditions, while also emphasizing the potential for common cutaneous adverse reactions to arise. The aim of this study is to investigate a multitude of impacting factors and determinants among patients presenting with ICI-associated cutaneous adverse reactions. Methods: We conducted a comprehensive analysis of ICI-associated cutaneous adverse reactions using data from the FAERS. Our study spans from January 1, 2015, to March 31, 2023, focusing on ICIs, including anti-PD-1, anti-PD-L1, and anti-CTLA-4 agents. Findings: Among the 334,293 reported irAR, 17,431 were identified as cutaneous adverse reactions (ARs). Predominant cutaneous ARs included rash (21.01 %), pruritus (11.22 %), and pemphigoid (3.90 %). Stevens-Johnson syndrome emerged as the most reported severe cutaneous adverse reaction (SCAR) (2.08 %). Anti-CTLA-4 agents exhibited higher cutaneous toxicity compared to anti-PD-1 and anti-PD-L1 agents. Anti-PD-1 agents demonstrated an elevated mortality rate. The combined use of ICIs with chemotherapy amplified the risk of SCAR and mortality. Targeted therapy was a risk factor for cutaneous ARs but was associated with reduced mortality. The median onset day for cutaneous toxicity was 21 days, while for SCAR, it was 23 days. Weight and age were identified as predictors of SCAR, cutaneous toxicity, and mortality. Skin cancer increased skin toxicity, while lung cancer heightened SCAR formation. The number of administered ICIs positively correlated with SCAR, skin toxicity, and mortality. Interpretation: This study highlights the significance of early identification and effective management of cutaneous toxicities, along with personalized follow-up care, as essential strategies for minimizing risks and preventing treatment disruptions.
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The role of proximal tubules (PTs), a major component of the renal tubular structure in the renal cortex, has been examined extensively. Along with its physiological role in the reabsorption of various molecules, including electrolytes, amino acids and monosaccharides, transcellular transport of different hormones and regulation of homeostasis, pathological events affecting PTs may underlie multiple disease states. PT hypertrophy or a hyperfunctioning state, despite being a compensatory mechanism at first in response to various stimuli or alterations at tubular transport proteins, have been shown to be critical pathophysiological events leading to multiple disorders, including diabetes mellitus, obesity, metabolic syndrome and congestive heart failure. Moreover, pharmacotherapeutic agents have primarily targeted PTs, including sodium-glucose cotransporter 2, urate transporters and carbonic anhydrase enzymes. In this narrative review, we focus on the physiological role of PTs in healthy states and the current understanding of the PT pathologies leading to disease states and potential therapeutic targets.
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OBJECTIVE: Kidney transplantation is the gold standard therapeutic alternative for patients with end-stage renal disease; nevertheless, it is not without potential complications leading to considerable morbidity and mortality such as post-transplant diabetes mellitus (PTDM). This narrative review aims to comprehensively evaluate PTDM in terms of its diagnostic approach, underlying pathophysiological pathways, epidemiological data, and management strategies. METHODS: Articles were retrieved from electronic databases using predefined search terms. Inclusion criteria encompassed studies investigating PTDM diagnosis, pathophysiology, epidemiology, and management strategies. RESULTS: PTDM emerges as a significant complication following kidney transplantation, influenced by various pathophysiological factors including peripheral insulin resistance, immunosuppressive medications, infections, and proinflammatory pathways. Despite discrepancies in prevalence estimates, PTDM poses substantial challenges to transplant. Diagnostic approaches, including traditional criteria such as fasting plasma glucose (FPG) and HbA1c, are limited in their ability to capture early PTDM manifestations. Oral glucose tolerance test (OGTT) emerges as a valuable tool, particularly in the early post-transplant period. Management strategies for PTDM remain unclear, within sufficient evidence from large-scale randomized clinical trials to guide optimal interventions. Nevertheless, glucose-lowering agents and life style modifications constitute primary modalities for managing hyperglycemia in transplant recipients. DISCUSSION: The complex interplay between PTDM and the transplant process necessitates individualized diagnostic and management approaches. While early recognition and intervention are paramount, modifications to maintenance immunosuppressive regimens based solely on PTDM risk are not warranted, given the potential adverse consequences such as increased rejection risk. Further research is essential to refine management strategies and enhance outcomes for transplant recipients.
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Diabetes Mellitus , Transplante de Rim , Humanos , Transplante de Rim/efeitos adversos , Fatores de Risco , Diabetes Mellitus/etiologia , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/terapia , Falência Renal Crônica/terapia , Falência Renal Crônica/cirurgia , Imunossupressores/uso terapêutico , Imunossupressores/efeitos adversos , Glicemia/metabolismo , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/terapia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/diagnóstico , Hipoglicemiantes/uso terapêutico , Teste de Tolerância a Glucose , Resistência à InsulinaRESUMO
Kidney transplantation, the gold-standard therapeutic approach for patients with end-stage kidney disease, offers improvement in patient survival and quality of life. However, broad sensitization against human leukocyte antigens often resulting in a positive crossmatch against the patient's living donor or the majority of potential deceased donors in the allocation system represents a major obstacle due to a high risk for antibody-mediated rejection, delayed graft function and allograft loss. Kidney-paired donation and desensitization protocols have been established to overcome this obstacle, with limited success. Imlifidase, a novel immunoglobulin G (IgG)-degrading enzyme derived from Streptococcus pyogenes and recombinantly produced in Escherichia coli, is a promising agent for recipients with a positive crossmatch against their organ donor with high specificity towards IgG, rapid action and high efficacy in early pre-clinical and clinical studies. However, the rebound of IgG after a few days can lead to antibody-mediated rejection, making the administration of potent immunosuppressive regimens in the early post-transplant phase necessary. There is currently no comparative study evaluating the efficiency of imlifidase therapy compared with conventional desensitization protocols along with the lack of randomized control trials, indicating the clear need for future large-scale clinical studies in this field. Besides providing a practical framework for the clinical use of the agent, our aim in this article is to evaluate the underlying mechanism of action, efficiency and safety of imlifidase therapy in immunologically high-risk kidney transplant recipients.
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Autosomal dominant polycystic kidney disease (ADPKD), the most common hereditary kidney disease, accounts for approximately 10% of the patients on kidney transplantation waitlists. High rates of complications including hemorrhage, infections, nephrolithiasis and kidney size-related compressive complaints have been reported among ADPKD patients. Therefore, the need for routine native nephrectomy and timing of such procedure in ADPKD patients being prepared for transplantation are debated. Even though pre-transplant nephrectomy has the potential to provide fewer infectious complications due to lack of immunosuppressive medication use, such procedure has been associated with longer hospital stay, loss of residual kidney function and need for dialysis. Although simultaneous nephrectomy and transplantation could potentially lead to longer perioperative duration, perioperative complications and need for blood transfusions, this was not confirmed in cohort studies. Therefore, some institutions routinely perform simultaneous unilateral nephrectomy and kidney transplantation. In this narrative review, our aim is to evaluate the current evidence regarding the need and timing of nephrectomy in ADPKD patients in relation to kidney transplantation.
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Klotho, a multifunctional protein, acts as a co-receptor in fibroblast growth factor 23 and exerts its impact through various molecular pathways, including Wnt, hypoxia-inducible factor and insulin-like growth factor 1 pathways. The physiological significance of Klotho is the regulation of vitamin D and phosphate metabolism as well as serving as a vital component in aging and neurodegeneration. The role of Klotho in aging and neurodegeneration in particular has gained considerable attention. In this narrative review we highlight several key insights into the molecular basis and physiological function of Klotho and synthesize current research on the role of Klotho in neurodegeneration and aging. Klotho deficiency was associated with cognitive impairment, reduced growth, diminished longevity and the development of age-related diseases in vivo. Serum Klotho levels showed a decline in individuals with advanced age and those affected by chronic kidney disease, establishing its potential diagnostic significance. Additionally, multiple medications have been demonstrated to influence Klotho levels. Therefore, this comprehensive review suggests that Klotho could open the door to novel interventions aimed at addressing the challenges of aging and neurodegenerative disorders.
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After the devastating earthquake in Türkiye and Syria in February, 2023, the long-term failure to meet the need for shelter, unfavourable living conditions in tent settlements, poor access to clean drinking water, water suitable for personal hygiene, and sanitary facilities, as well as interruptions in provision of primary health-care services, have emerged as the most important risk factors contributing to the spread of infectious diseases. 3 months after the earthquake, most of these problems persist in Türkiye. Data on the control of infectious diseases are scarce according to the reports prepared by medical specialist associations based on observations of health-care providers working in the region and statements made by the local health authorities. According to these unsystematised data, and considering the conditions in the region, faecal-oral transmissible gastrointestinal infections, as well as respiratory and vector-borne infections, are the main challenges. Vaccine-preventable diseases, such as measles, varicella, meningitis, and polio can be spread in temporary shelters due to interrupted vaccine services and crowded living conditions. In addition to controlling risk factors for infectious diseases, sharing data on the status and control of infectious diseases in the region with the community, health-care providers, and relevant expert groups should be a priority to improve the understanding of the effects of interventions and prepare for possible infectious disease outbreaks.
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Doenças Transmissíveis , Terremotos , Humanos , Doenças Transmissíveis/epidemiologia , Surtos de Doenças , Serviços de Saúde , SíriaRESUMO
BACKGROUND: Mucormycosis, a rare fungal infection, has shown an increase in the number of reported cases during the COVID-19 pandemic. OBJECTIVES: To provide a comprehensive insight into the characteristics of COVID-19-associated mucormycosis, through a systematic review and meta-analysis. METHODS OF DATA SYNTHESIS: Demographic information and clinical features were documented for each patient. Logistic regression analysis was used to predict the risk of mortality. DATA SOURCES: PubMed, Scopus, Web of Science, Cochrane, CINAHL, Ovid MEDLINE, and FungiSCOPE. STUDY ELIGIBILITY CRITERIA: Studies reporting individual-level information in patients with adult COVID-19-associated mucormycosis (CAM) between 1 January 2020 and 28 December 2022. PARTICIPANTS: Adults who developed mucormycosis during or after COVID-19. INTERVENTIONS: Patients with and without individual clinical variables were compared. ASSESSMENT OF RISK OF BIAS: Quality assessment was performed based on the National Institutes of Health quality assessment tool for case series studies. RESULTS: Nine hundred fifty-eight individual cases reported from 45 countries were eligible. 88.1% (844/958) were reported from low- or middle-income countries. Corticosteroid use for COVID-19 (78.5%, 619/789) and diabetes (77.9%, 738/948) were common. Diabetic ketoacidosis (p < 0.001), history of malignancy (p < 0.001), underlying pulmonary (p 0.017), or renal disease (p < 0.001), obesity (p < 0.001), hypertension (p 0.040), age (>65 years) (p 0.001), Aspergillus coinfection (p 0.037), and tocilizumab use during COVID-19 (p 0.018) increased the mortality. CAM occurred on an average of 22 days after COVID-19 and 8 days after hospitalization. Diagnosis of mucormycosis in patients with Aspergillus coinfection and pulmonary mucormycosis was made on average 15.4 days (range, 0-35 days) and 14.0 days (range, 0-53 days) after hospitalization, respectively. Cutaneous mucormycosis accounted for <1% of the cases. The overall mortality rate was 38.9% (303/780). CONCLUSION: Mortality of CAM was high, and most reports were from low- or middle-income countries. We detected novel risk factors for CAM, such as older age, specific comorbidities, Aspergillus coinfection, and tocilizumab use, in addition to the previously identified factors.