Advancing kidney transplant outcomes: the role of urinary proteomics in graft function monitoring and rejection detection.

INTRODUCTION: Kidney transplantation significantly improves the lives of those with end-stage kidney disease, offering best alternative to dialysis. However, transplant success is threatened by the acute and chronic rejection mechanisms due to complex immune responses against the new organ. AREAS COVERED: The ongoing research into biomarkers holds promise for revolutionizing the early detection and monitoring of the graft health. Liquid biopsy techniques offer a new avenue, with several diagnostic, predictive, and prognostic biomarkers showing promise in detecting and monitoring kidney diseases and an early and chronic allograft rejection. EXPERT OPINION: Evaluating the protein composition related to kidney transplant results could lead to identifying biomarkers that provide insights into the graft functionality. Non-invasive proteomic biomarkers can drastically enhance clinical outcomes and change the way how kidney transplants are evaluated for patients and physicians if they succeed in this transition. Hence, the advancement in proteomic technologies, leads toward a significant improvement in understanding of the protein markers and molecular mechanisms linked to the outcomes of kidney transplants. However, the road from discovery to the use of such proteins in clinical practice is long, with a need for continuous validation and beyond the singular research team with comprehensive infrastructure and across research groups collaboration.

Phosphate in the Context of Cognitive Impairment and Other Neurological Disorders Occurrence in Chronic Kidney Disease.

The nervous system and the kidneys are linked under physiological states to maintain normal body homeostasis. In chronic kidney disease (CKD), damaged kidneys can impair the central nervous system, including cerebrovascular disease and cognitive impairment (CI). Recently, kidney disease has been proposed as a new modifiable risk factor for dementia. It is reported that uremic toxins may have direct neurotoxic (astrocyte activation and neuronal death) and/or indirect action through vascular effects (cerebral endothelial dysfunction, calcification, and inflammation). This review summarizes the evidence from research investigating the pathophysiological effects of phosphate toxicity in the nervous system, raising the question of whether the control of hyperphosphatemia in CKD would lower patients' risk of developing cognitive impairment and dementia.

Brain dysfunction in tubular and tubulointerstitial kidney diseases.

Kidney function has two important elements: glomerular filtration and tubular function (secretion and reabsorption). A persistent decrease in glomerular filtration rate (GFR), with or without proteinuria, is diagnostic of chronic kidney disease (CKD). While glomerular injury or disease is a major cause of CKD and usually associated with proteinuria, predominant tubular injury, with or without tubulointerstitial disease, is typically non-proteinuric. CKD has been linked with cognitive impairment, but it is unclear how much this depends on a decreased GFR, altered tubular function or the presence of proteinuria. Since CKD is often accompanied by tubular and interstitial dysfunction, we explore here for the first time the potential role of the tubular and tubulointerstitial compartments in cognitive dysfunction. To help address this issue we selected a group of primary tubular diseases with preserved GFR in which to review the evidence for any association with brain dysfunction. Cognition, mood, neurosensory and motor disturbances are not well characterized in tubular diseases, possibly because they are subclinical and less prominent than other clinical manifestations. The available literature suggests that brain dysfunction in tubular and tubulointerstitial diseases is usually mild and is more often seen in disorders of water handling. Brain dysfunction may occur when severe electrolyte and water disorders in young children persist over a long period of time before the diagnosis is made. We have chosen Bartter and Gitelman syndromes and nephrogenic diabetes insipidus as examples to highlight this topic. We discuss current published findings, some unanswered questions and propose topics for future research.

Neuropeptide Y as a risk factor for cardiorenal disease and cognitive dysfunction in chronic kidney disease: translational opportunities and challenges.

Neuropeptide Y (NPY) is a 36-amino-acid peptide member of a family also including peptide YY and pancreatic polypeptide, which are all ligands to Gi/Go coupled receptors. NPY regulates several fundamental biologic functions including appetite/satiety, sex and reproduction, learning and memory, cardiovascular and renal function and immune functions. The mesenteric circulation is a major source of NPY in the blood in man and this peptide is considered a key regulator of gut-brain cross talk. A progressive increase in circulating NPY accompanies the progression of chronic kidney disease (CKD) toward kidney failure and NPY robustly predicts cardiovascular events in this population. Furthermore, NPY is suspected as a possible player in accelerated cognitive function decline and dementia in patients with CKD and in dialysis patients. In theory, interfering with the NPY system has relevant potential for the treatment of diverse diseases from cardiovascular and renal diseases to diseases of the central nervous system. Pharmaceutical formulations for effective drug delivery and cost, as well as the complexity of diseases potentially addressable by NPY/NPY antagonists, have been a problem until now. This in part explains the slow progress of knowledge about the NPY system in the clinical arena. There is now renewed research interest in the NPY system in psychopharmacology and in pharmacology in general and new studies and a new breed of clinical trials may eventually bring the expected benefits in human health with drugs interfering with this system.

Exhausting multiple hemodialysis access failures.

INTRODUCTION: Vascular access is often considered the Achilles heel the of hemodialysis because of its impact on morbidity, all cause mortality and finally costs of these patients. The most common complication of permanent hemodialysis (HD) vascular access is thrombosis, with some cases being related to hypercoagulability states. Antiphospholipid antibody syndrome (APAS) is a cause of increased thrombotic tendency, and this may complicate the management of such patients on HD. CASE REPORT: We describe a 41-year-old woman with end stage renal disease (ESRD) from Adult Polycystic Kidney Disease who was referred to our tertiary care center for treatment and selection of renal replacement therapy form. It was thought to initiate with peritoneal dialysis considering her actual conditions. She was putted on hemodialysis for several sessions, and a subclavian cathether was her first vascular access. The surgeon created an arterio-venous fistula which did not mature. After the implantation of the peritoneal cathether she started peritoneal dialysis and continued living with that for 2 years. She felt exhausted and because of a grave peritonitis episode accompanied with procedure failure and a long hospitalization she was transferred to hemodialysis. Renal transplantation was not possible because she didn't have a kidney donation. She was maintained on regular HD, but her dialysis care was complicated by recurrent vascular access failures. She had multiple interventions for arterio-venous fistulas and grafts but almost all of them failed due to thrombosis to the extent that only one access site was available for her routine renal replacement treatment. A thorough thrombophilia screen confirmed the presence of antiphospholipid antibodies. A diagnosis of APAS was made and she was anticoagulated with warfarin. The AVG made in this last available site is still working from 18 months. If it fails we have no answers and solutions for her. CONCLUSION: The presence of APAS can complicate HD management by causing recurrent vascular access thrombosis and failure, and nephrologist must remain alert to this possibility. Checking and treating as soon as possible it's our future challenge.

Transforming Diabetes Care: The Molecular Pathways through Which GLP1-RAs Impact the Kidneys in Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is a substantial complication of type 2 diabetes (T2D), presenting challenges in chronic kidney disease (CKD) management. In addition to traditional and recent therapies, including angiotensin, converting enzyme (ACE) inhibitors, angiotensin receptor blockers, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and mineralocorticoid receptor antagonists, the evolution of antihyperglycemic treatments has introduced a promising agent, glucagon-like peptide-1 receptor agonist (GLP-1RA) for the management of DKD. GLP-1RAs enhance insulin release and reduce glucagon release, offering a novel approach to DKD management. This review analyzes the molecular pathways through which GLP1-RAs confer renal protection in T2D and DKD, which are complex and multifaceted. They include modulation of renal hemodynamics, antioxidative and anti-inflammatory actions, metabolic regulation, and direct cellular effects. These mechanisms highlight GLP1-RA's potential as a therapeutic option for glycemic control and direct or indirect renal function protection in diabetic patients, emphasizing the potentiality of GLP-1RAs for dual therapy, with cardiovascular and renal protection as a holistic approach. Clinical evidence supports GLP-1RAs in reducing albuminuria and enhancing kidney outcomes, highlighting their value in a comprehensive DKD management strategy.

Carnitine Palmitoyltransferase II (CPT2) Deficiency: An Overlooked and Elusive Cause of Acute Kidney Injury.

Carnitine palmitoyltransferase II (CPT2) deficiency is a rare inherited disorder affecting fatty acid metabolism. This enzymatic defect presents with a broad clinical spectrum, from severe neonatal forms that can be fatal, to milder myopathic variants characterized by myalgia and recurrent myoglobinuria in adolescence and adulthood. Herein, we report the case of a male patient who developed exertional rhabdomyolysis and acute kidney injury due to CPT2 deficiency. This case underscores the importance of considering genetic disorders in the differential diagnosis of patients presenting with recurrent exercise intolerance and metabolic crises. Early recognition and diagnosis enable prompt implementation of dietary and lifestyle modifications aimed at mitigating potential complications such as renal impairment. Moreover, timely diagnosis allows for genetic counseling of affected individuals and their families.

Sodium and water dynamics in the progression of chronic kidney disease: mechanisms and clinical significance.

AIM: Lifestyle modifications can postpone the progression of chronic kidney disease toward its terminal stage. This mini-review aims to explore the impact of salt and water intake on the progression of chronic kidney disease (CKD) and provide insights into the optimal consumption levels to preserve the glomerular filtration rate. METHODS: We reviewed relevant literature to examine the association between salt and water consumption and CKD progression. Our analysis includes discussions on the pathophysiology, findings from clinical trials, and recommended intake guidelines. RESULTS: Sodium intake, often linked to cardiovascular risk and CKD progression, has shown a complex J-shaped association in some studies, leading to uncertainty about the ideal salt intake level. Sodium and fluid retention are key factors contributing to hypertension, a well-established risk factor for CKD progression. Low-sodium diets have demonstrated promise in reducing blood pressure and enhancing the effects of renin-angiotensin-aldosterone system inhibitors in non-dialysis CKD patients. However, a debate persists regarding the independent effect of salt restriction on CKD progression. Despite medical recommendations, salt consumption remains high among CKD patients. Additionally, the role of water consumption in CKD remains controversial despite its established benefits for CKD prevention in the general population. CONCLUSION: Lifestyle modifications involving salt and water intake can influence the progression of CKD. While low-sodium diets have shown potential for mitigating hypertension and proteinuria in non-dialysis CKD patients, their independent impact on CKD progression warrants further investigation. The role of water consumption in CKD remains uncertain, and there is a need for additional research in this area. Clinicians should consider individualized dietary recommendations for CKD patients to help preserve the glomerular filtration rate and improve overall outcomes.

A New Hope on the Horizon for Kidney and Cardiovascular Protection with SGLT2 Inhibitors, GLP-1 Receptor Agonists, and Mineralocorticoid Receptor Antagonists in Type 2 Diabetic and Chronic Kidney Disease Patients.

Type 2 diabetes (T2D) is the leading cause of chronic kidney disease (CKD). In addition, the cardiovascular prevalence in diabetic patients is around 32.2%, with a two-fold increased mortality risk compared to those without diabetes. Recent investigations have shed light on the promising cardioprotective and nephroprotective benefits of sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and nonsteroidal mineralocorticoid receptor antagonists (nsMRAs) for individuals with T2D. The evidence robustly indicates that SGLT2i and GLP-1RA significantly reduce the risk of CKD and cardiovascular disease (CVD), all while effectively managing blood glucose levels. Furthermore, combining SGLT2i with nsMRAs amplifies the benefits, potentially offering a more profound reduction in cardiovascular and renal outcomes. The data analysis strongly supports the integration of these pharmacological agents in the management strategies for CKD and CVD prevention among T2D patients, highlighting the importance of awareness among nephrologists, especially in regions with limited healthcare resources.

FGF23 in Chronic Kidney Disease: Bridging the Heart and Anemia.

Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone produced mainly in osteocytes. In chronic kidney disease (CKD) FGF23 levels increase due to higher production, but also as the result of impaired cleavage and reduced excretion from the body. FGF23 has a significant role in disturbed bone and mineral metabolism in CKD, which leads to a higher cardiovascular risk and mortality in these patients. Current research has emphasized the expression of FGF23 in cardiac myocytes, fibroblasts, and endothelial cells, and in addition to the effects on the kidney, its primary role is in cardiac remodeling in CKD patients. Recent discoveries found a significant link between increased FGF23 levels and anemia development in CKD. This review describes the FGF23 role in cardiac hypertrophy and anemia in the setting of CKD and discusses the best therapeutical approach for lowering FGF23 levels.

Proteomic Approaches and Potential Applications in Autosomal Dominant Polycystic Kidney Disease and Fabry Disease.

Although rare, hereditary diseases, such as autosomal dominant polycystic kidney disease (ADPKD) and Fabry disease (FD) may significantly progress towards severe nephropathy. It is crucial to characterize it accurately, predict the course of the illness and estimate treatment effectiveness. A huge effort has been undertaken to find reliable biomarkers that might be useful for an early prevention of the disease progression and/or any invasive diagnostic procedures. The study of proteomics, or the small peptide composition of a sample, is a field of study under continuous development. Over the past years, several strategies have been created to study and define the proteome of samples from widely varying origins. However, urinary proteomics has become essential for discovering novel biomarkers in kidney disease. Here, the extracellular vesicles in human urine that contain cell-specific marker proteins from every segment of the nephron, offer a source of potentially valuable urinary biomarkers, and may play an essential role in kidney development and kidney disease. This review summarizes the relevant literature investigating the proteomic approaches and potential applications in the regular studies of ADPKD and FD.

Subclinical Hypothyroidism, Kidney, and Heart from Normal to Uremic Milieu.

Thyroid hormone (TH) imbalances, particularly subclinical hypothyroidism (SCHT), are associated with chronic kidney disease (CKD) and end-stage kidney disease (ESKD). SCHT is more prevalent in CKD and ESKD patients than in the general population, and this condition increases the risk of cardiovascular disease (CVD) morbidity and mortality. The risk of CVD is higher in CKD and ESKD patients compared with the general population. Traditional and nontraditional risk factors, including TH abnormalities, contribute to the high CVD burden in CKD and ESKD patients. The review discusses the link between CKD and hypothyroidism, with a focus on SCHT, and the mechanisms that lead to CVD burden.

The Role of Protein Restriction in the Progression of Chronic Kidney Disease.

Even though nephrology has made much progress, reducing the progression of the chronic kidney disease remains, in fact, one of the biggest challenges. Long before the renal replacement therapy (RRT), it was known that limiting the protein could help almost all uremia symptoms. Although it was proposed as early as the 1960s, it only became widely used in the 1980s. By lowering the urea and other nitrogen wastes and lowering the metabolic acidosis, oxidative stress, and insulin resistance, limiting the amount of protein in your diet can help improve uremic symptoms. Also, limiting the protein in the diet positively controls the cardiovascular complications, including the arterial blood pressure and proteinuria reduction, which are risk factors for CKD progression. This mini-review examines the impact of protein restriction on the possibility of slowing CKD progression in depth.

The Complexity of FGF23 Effects on Cardiomyocytes in Normal and Uremic Milieu.

Fibroblast growth factor-23 (FGF23) appears to be one of the most promising biomarkers and predictors of cardiovascular risk in patients with heart disease and normal kidney function, but moreover in those with chronic kidney disease (CKD). This review summarizes the current knowledge of FGF23 mechanisms of action in the myocardium in the physiological and pathophysiological state of CKD, as well as its cross-talk to other important signaling pathways in cardiomyocytes. In this regard, current therapeutic possibilities and future perspectives are also discussed.

The potential effect of cardiac function on pulmonary hypertension, other risk factors, and its impact on survival in dialysis patients.

INTRODUCTION: Pulmonary hypertension (PH) is a recently recognized as a complication of chronic kidney disease and end-stage renal disease. The pathogenesis of pulmonary hypertension in this group of patients is not fully understood, probably due to the interaction of multiple aspects of the altered cardiovascular physiology and also hormonal and metabolic disorders. The present study aimed to determine the prevalence of PH, correlation with cardiac function and other risk factors and its impact of survival in chronic hemodialysis and peritoneal dialysis patients. METHODS: We studied 125 stable hemodialysis and peritoneal patients (females 40%, mean age 52.42 ± 11.88 years) on renal replacement therapy (RRT) for more than 3 months with a follow up 2 years. Demographic information, clinical characteristics, blood test, and thoroughly echocardiographic evaluation at the optimal dry weight were collected. After conventional echocardiographic examination, tissue Doppler echocardiographic (TDE) examination was performed to evaluate global and regional myocardial systolic as well as diastolic function, and pulmonary hypertension. PH was defined as systolic pulmonary artery pressure (sPAP) ≥ 35 mmHg. To rule out secondary PH, patients with pulmonary disease, collagen vascular disease, and volume overload at the time of echocardiography were excluded. Variables were compared between two groups-subjects with PH and non-PH. Logistic regression analysis was used to evaluate the risk factor for PH and its impact on survival. RESULTS: According to the echocardiographic findings, PH was found in 28% (35 patients) of all patients. Mean PH was 33.46 ± 5.38 mmHg. The higher level of higher parathormone (PTH), C-reactive protein (CRP) and E/E' average, lower left ventricular ejection fraction (EF), peak systolic velocity at the lateral mitral annulus (MASa) and the peak systolic velocity at the lateral tricuspid annulus (TASa) were found predictor of PH. The cardiovascular mortality rate was 15.5%. Patients evaluated with PH have a significantly lower cardiovascular survival rate [Long Rank (Mantel-Cox) p = 0.0001]. In ROC analysis for CV mortality, the area under the curve (AUC) for PH and CRP was found 0.8; for LVM-I, E/E' and PP, AUC = 0.76; 0.75; 0.72 respectively while the inverse relationship was found with MASa and TASa with AUC = 0.66 and 0.95 respectively. CONCLUSION: Our study shows that PH is frequent in dialysis patients. It is influenced by inflammation, CKD-MBD biomarkers associated with diastolic and also systolic left and right ventricle dysfunction. Pulmonary hypertension, inflammation, vascular stiffness, and left ventricular hypertrophy are interrelated and all contribute to cardiovascular morbidity and mortality among dialysis patients. Easy to implement, cardiac imaging at the bedside and in outpatient clinics offers a positive perspective in early diagnosis of cardiac abnormalities and immediate approach to this condition, so is highly recommended in the dialysis population.

Sclerostin: a new biomarker of CKD-MBD.

The causes of the increased cardiovascular risk associated with kidney diseases partly reside in the chronic kidney disease-mineral bone disorder (CKD-MBD) syndrome. Three cardiovascular risk factors [hyperphosphatemia, vascular calcification, and elevated fibroblast growth factor 23 (FGF23)] levels have been discovered within the CKD-MBD over the last decades. In addition, sclerostin is recently presented as a new bone and vascular disease biomarker. This 22-kDa glycoprotein, secreted mainly by osteocytes, is a soluble inhibitor of the canonical Wnt pathway that has a pivotal role in bone biology and turnover. CKD patients are reported with higher levels of sclerostin, and levels decrease during dialysis. Sclerostin is associated with vascular calcification and CV risk in CKD, although data are still controversial. The question whether serum sclerostin has protective or deleterious role in CKD-MBD pathophysiology, and therefore in cardiovascular risk and overall mortality, is still open and needs to be answered. The standardization of assays and the establishment of a clear cut-off values when sclerostin starts to switch from physiological to pathophysiological role have to be another important step. Further research is needed also to define its relationship with other CKD-MBD biomarkers for future diagnostic and therapeutic strategies.

Should We Consider the Cardiovascular System While Evaluating CKD-MBD?

Cardiovascular (CV) disease is highly prevalent in the population with chronic kidney disease (CKD), where the risk of CV death in early stages far exceeds the risk of progression to dialysis. The presence of chronic kidney disease-mineral and bone disorder (CKD-MBD) has shown a strong correlation with CV events and mortality. As a non-atheromatous process, it could be partially explained why standard CV disease-modifying drugs do not provide such an impact on CV mortality in CKD as observed in the general population. We summarize the potential association of CV comorbidities with the older (parathyroid hormone, phosphate) and newer (FGF23, Klotho, sclerostin) CKD-MBD biomarkers.

Influence of Residual Renal Function in Carotid Modeling as a Marker of Early Atherosclerosis in Dialysis Patients.

Atherosclerosis is frequently present in patients with chronic kidney disease (CKD) treated with dialysis. We evaluated the association between residual renal function (RRF), phosphate level, inflammation and other risk factors in carotid modeling as a marker of early atherosclerosis in peritoneal dialysis (PD) compared with hemodialysis (HD) patients. We studied 39 stable PD and 53 HD patients on renal replacement therapy (RRT) for 3 to 36 months duration. B-mode ultrasonography was used to determine carotid artery intima media thickness (CIMT). We classified patients with atherosclerosis if they have CIMT >10 mm and or presence of plaque. Out of our total dialysis population studied of 92 patients, 16.3% were diabetics and 57.6% were on hemodialysis. Expectedly, PD patients had a higher RRF (P < 0.001), 24 h urine volume (P < 0.001); C-reactive protein (P = 0.047), and a lower serum phosphate (P = 0.01), PTH (P < 0.05), alkaline phosphatase (P < 0.05), and albumin levels (P < 0.001) compared to hemodialysis patients. Atherosclerosis was found in 66.3% of patients and in 100% of a diabetic population. There was no significant difference in the presence of atherosclerosis between PD and HD patients [56.4 vs 73.6% HD, respectively]. Multiple regression analysis showed age, diabetes, HD modality, RRF, phosphate, PTH and pulse pressure as independent parameters associated with atherosclerosis. Apart from the traditional risk factors like age and diabetes, our study showed a link of atherosclerosis with metabolic abnormalities secondary to renal failure. We demonstrated a novel, independent association between RRF and atherosclerosis, underlining the importance of preservation of the RRF in dialysis patients.

Association of kidney fibrosis with urinary peptides: a path towards non-invasive liquid biopsies?

Chronic kidney disease (CKD) is a prevalent cause of morbidity and mortality worldwide. A hallmark of CKD progression is renal fibrosis characterized by excessive accumulation of extracellular matrix (ECM) proteins. In this study, we aimed to investigate the correlation of the urinary proteome classifier CKD273 and individual urinary peptides with the degree of fibrosis. In total, 42 kidney biopsies and urine samples were examined. The percentage of fibrosis per total tissue area was assessed in Masson trichrome stained kidney tissues. The urinary proteome was analysed by capillary electrophoresis coupled to mass spectrometry. CKD273 displayed a significant and positive correlation with the degree of fibrosis (Rho = 0.430, P = 0.0044), while the routinely used parameters (glomerular filtration rate, urine albumin-to-creatinine ratio and urine protein-to-creatinine ratio) did not (Rho = -0.222; -0.137; -0.070 and P = 0.16; 0.39; 0.66, respectively). We identified seven fibrosis-associated peptides displaying a significant and negative correlation with the degree of fibrosis. All peptides were collagen fragments, suggesting that these may be causally related to the observed accumulation of ECM in the kidneys. CKD273 and specific peptides are significantly associated with kidney fibrosis; such an association could not be detected by other biomarkers for CKD. These non-invasive fibrosis-related biomarkers can potentially be implemented in future trials.