Animal models to study cognitive impairment of chronic kidney disease.

Mild cognitive impairment (MCI) is common in people with chronic kidney disease (CKD), and its prevalence increases with progressive loss of kidney function. MCI is characterized by a decline in cognitive performance greater than expected for an individual age and education level but with minimal impairment of instrumental activities of daily living. Deterioration can affect one or several cognitive domains (attention, memory, executive functions, language, and perceptual motor or social cognition). Given the increasing prevalence of kidney disease, more and more people with CKD will also develop MCI causing an enormous disease burden for these individuals, their relatives, and society. However, the underlying pathomechanisms are poorly understood, and current therapies mostly aim at supporting patients in their daily lives. This illustrates the urgent need to elucidate the pathogenesis and potential therapeutic targets and test novel therapies in appropriate preclinical models. Here, we will outline the necessary criteria for experimental modeling of cognitive disorders in CKD. We discuss the use of mice, rats, and zebrafish as model systems and present valuable techniques through which kidney function and cognitive impairment can be assessed in this setting. Our objective is to enable researchers to overcome hurdles and accelerate preclinical research aimed at improving the therapy of people with CKD and MCI.

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.

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.

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.

Albuminuria as a risk factor for mild cognitive impairment and dementia-what is the evidence?

Kidney dysfunction can profoundly influence many organ systems, and recent evidence suggests a potential role for increased albuminuria in the development of mild cognitive impairment (MCI) or dementia. Epidemiological studies conducted in different populations have demonstrated that the presence of increased albuminuria is associated with a higher relative risk of MCI or dementia both in cross-sectional analyses and in studies with long-term follow-up. The underlying pathophysiological mechanisms of albuminuria's effect are as yet insufficiently studied, with several important knowledge gaps still present in a complex relationship with other MCI and dementia risk factors. Both the kidney and the brain have microvascular similarities that make them sensitive to endothelial dysfunction involving different mechanisms, including oxidative stress and inflammation. The exact substrate of MCI and dementia is still under investigation, however available experimental data indicate that elevated albuminuria and low glomerular filtration rate are associated with significant neuroanatomical declines in hippocampal function and grey matter volume. Thus, albuminuria may be critical in the development of cognitive impairment and its progression to dementia. In this review, we summarize the available evidence on albuminuria's link to MCI and dementia, point to existing gaps in our knowledge and suggest actions to overcome them. The major question of whether interventions that target increased albuminuria could prevent cognitive decline remains unanswered. Our recommendations for future research are aimed at helping to plan clinical trials and to solve the complex conundrum outlined in this review, with the ultimate goal of improving the lives of patients with chronic kidney disease.

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.

Heparin-binding protein as a novel biomarker for sepsis-related acute kidney injury.

BACKGROUND: Sepsis-related acute kidney injury (AKI) is associated with high morbidity and mortality among patients. Underlying pathomechanisms include capillary leakage and fluid loss into the interstitial tissue and constant exposure to pathogens results in activation of inflammatory cascades, organ dysfunction and subsequently organ damage. METHODS: To identify novel factors that trigger sepsis-related acute kidney injury, plasma levels of Granzyme A, as representative of a lymphocyte-derived protease, and heparin-binding protein as indicator for neutrophil-derived mediators, were investigated retrospectively in 60 sepsis patients. RESULTS: While no association was found between plasma levels of lymphocyte-derived Granzyme A and the incidence of sepsis-related AKI, sepsis patients with AKI had significantly higher plasma levels of heparin-binding protein compared to those without AKI. This applies both to heparin-binding protein peak values (43.30 ±  23.34 vs. 30.25 ±  15.63 pg/mL; p = 0.005) as well as mean values (27.93 ±  14.39 vs. 22.02 ±  7.65 pg/mL; p = 0.021). Furthermore, a heparin-binding protein cut-off value of 23.89 pg/mL was established for AKI diagnosis. CONCLUSION: This study identifies the neutrophil-derived heparin-binding protein as a valuable new biomarker for AKI in sepsis. Beyond the diagnostic perspective, this offers prospect for further research on pathogenesis of AKI and novel therapeutic approaches.

Quantitative intravital Ca2+ imaging maps single cell behavior to kidney tubular structure.

Ca2+ is an important second messenger that translates extracellular stimuli into intracellular responses. Although there has been significant progress in understanding Ca2+ dynamics in organs such as the brain, the nature of Ca2+ signals in the kidney is still poorly understood. Here, we show that by using a genetically expressed highly sensitive reporter (GCaMP6s), it is possible to perform imaging of Ca2+ signals at high resolution in the mouse kidney in vivo. Moreover, by applying machine learning-based automated analysis using a Ca2+-independent signal, quantitative data can be extracted in an unbiased manner. By projecting the resulting data onto the structure of the kidney, we show that different tubular segments display highly distinct spatiotemporal patterns of Ca2+ signals. Furthermore, we provide evidence that Ca2+ activity in the proximal tubule decreases with increasing distance from the glomerulus. Finally, we demonstrate that substantial changes in intracellular Ca2+ can be detected in proximal tubules in a cisplatin model of acute kidney injury, which can be linked to alterations in cell structure and transport function. In summary, we describe a powerful new tool to investigate how single cell behavior is integrated with whole organ structure and function and how it is altered in disease states relevant to humans.

A Systematic Review of Renal Functional Reserve in Adult Living Kidney Donors.

INTRODUCTION: The kidney's capacity to increase its glomerular filtration rate (GFR) in response to a higher functional demand is known as the renal functional reserve (RFR). Good short-term outcomes after living kidney donation have led to more acceptance of borderline donors (with hypertension, obesity, older age) due the ongoing shortage of donor organs. Given recent concerns about increased long-term risk in some donor subgroups, better donor stratification is needed. Measurement of RFR could inform assessment of donor risk. METHODS: A systematic literature review of studies that assessed RFR in donors pre- and/or post-donation was performed. Given study heterogeneity, descriptive analysis and narrative synthesis was conducted. RESULTS: Sixteen of 3250 identified studies published between 1956 and 2019 met inclusion criteria. Most studies were cross-sectional and conducted before (n = 8) and/or after (n = 16) kidney donation. Methods for measurement of GFR, effective renal plasma flow (ERPF) and RFR were not standardized. Changes in filtration fraction (FF) and ERPF relative to GFR observed after donation varied depending on stimulus used to induce RFR. Overall, RFR fell after donation; however, over the shorter term, RFR was largely preserved in young healthy donors. RFR was more significantly reduced in donors with hypertension, obesity, or older age. CONCLUSION: Existing data suggest possible blunting of RFR post-donation in older, obese, and hypertensive donors, which may represent increased single-nephron GFR at baseline. The long-term implications of these changes deserve further study to determine utility in informing selection of borderline kidney donors.

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.

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.

Non-Diabetic Kidney Disease in Patients with Type 2 Diabetes Mellitus-11-Year Experience from a Single Center.

INTRODUCTION: In patients with diabetes mellitus (DM), non-diabetic renal disease (NDRD) can also occurs, as well as diabetic nephropathy. NDRD is most accurately diagnosed using kidney biopsy. AIM: The aim of the study was to investigate the incidence and type of NDRD diagnosed by kidney biopsy in patients with type 2 DM and the correlation of clinical and laboratory findings with histopathological diagnosis. MATERIAL AND METHODS: From April 2007 to October 2018, 290 kidney biopsies were performed at the Department of Nephrology, Internal Medicine Clinic in Banja Luka, out of which 18 patients (males 9, mean age 59.8 years) were with type 2 DM. The US-guided (ultrasound device: Toshiba Famio 5) kidney biopsy was performed using an automatic biopsy instrument FAST-GUN® with needle 16G. Kidney tissue samples were analyzed by light microscopy and immunofluorescence. RESULTS: In 18 patients with type 2 DM, the average duration of the disease was 5.9 years, 5 patients had a retinopathy, and 16 patients had hypertension. Biopsy indications were: nephrotic syndrome in 11 patients, asymptomatic urinary abnormalities in 3 patients, and rapid chronic renal failure progression. Unsatisfactory quality sample for pathohistological analysis was obtained in one patient, and out of the other 17, 6 (35.3%) had NDRD, 3 (17.6%) had NDRD superimposed with the diabetic nephropathy, and 8 (47.1%) had diabetic nephropathy. Of the patients who had NDRD, 3 had membranous glomerulonephritis, 1 had focal segmental glomerulosclerosis, and two had hypertensive nephroangiosclerosis. Out of patients with coexisting NDRD and diabetic nephropathy, 2 had hypertensive nephroangiosclerosis and one diabetic nephropathy and lupus nephritis. CONCLUSION: NDRD was diagnosed using kidney biopsy in 9/17 patients with type 2 DM, which confirms the significance of the kidney biopsy in patients with DM with properly indications. Accurate diagnosis provides disease specific treatment and thus significantly improves the long-term prognosis of the patient.

Is serum sclerostin a marker of atherosclerosis in patients with chronic kidney disease-mineral and bone disorder?

PURPOSE: The complexity of chronic kidney disease-mineral and bone disorder (CKD-MBD) led to many preclinical and clinical trials. The role of sclerostin in renal pathophysiology remained unresolved, and question whether sclerostin is related to cardiovascular (CV) outcome in patients with CKD is still open. Our aim was to evaluate the possible association between serum sclerostin levels and carotid intima-media thickness (CIMT) in CV pathophysiology through various CKD stages. METHODS: Eighty-eight patients in various CKD stages were involved in this analysis. CKD-EPI (Chronic kidney disease Epidemiology Collaboration Equation) was used to estimate glomerular filtration rate (eGFR). CKD-MBD parameters were determined in patients' serum after an overnight fasting. Early atherosclerosis was assessed by ultrasound measurement of CIMT. In order to assess the association between serum sclerostin with other CKD-MBD parameters and CIMT, correlation and regression analyses were performed. RESULTS: Mean age was 62.84 ± 11.37 years and 56% were female. Mean values of serum sclerostin were 1.67 ± 0.44 ng/ml. Negative correlation was noticed with serum calcium and phosphate product (CaxP), alkaline phosphatase (ALP), intact parathyroid hormone (iPTH), serum creatinine, and HbA1c level. There was no association with FGF23, CIMT, and carotid atherosclerotic plaque occurence. Serum levels of sclerostin were significantly higher in female patients compared to males (p < 0.001). CONCLUSION: Advanced CKD showed a trend of declining sclerostin levels and significantly higher CIMT levels. Serum sclerostin was not associated with CIMT. More studies are needed in order to reveal the exact role of sclerostin in the complexity of CKD-MBD pathophysiological mechanism.

FGF23 Level and Intima-Media Thickness Are Elevated From Early Stages of Chronic Kidney Disease.

Considering high cardiovascular (CV) risk in chronic kidney disease (CKD), the aim of this cross-sectional study was to assess the association between carotid intima-media thickness (IMT) and fibroblast growth factor (FGF) 23 as important players in CV pathophysiology. Eighty-seven patients with mean estimated glomerular filtration rate 40.1 mL/min per 1.73 m2 were involved. FGF23 and IMT were elevated from early stages of CKD. Mean IMT value was 1.10 ± 0.20 mm, being significantly elevated starting from early CKD, showing no correlation with FGF23 (r = -0.01, P = -0.91). Unlike the FGF23 level that followed worsening of kidney function, IMT was increasing only in the initial CKD stages, with no further increase from CKD stage 3 on. Although we found no direct association between current use of vitamin D and statin therapy, this may be associated with the sustained reference values of lipid and vitamin D status under treatment that further preclude worsening of IMT in patients with advanced CKD.

The frequency of bone fractures among patients with chronic kidney disease not on dialysis: two-year follow-up.

INTRODUCTION: Renal osteodystrophy is a severe complication of chronic kidney disease (CKD) that increases morbidity and mortality in these patients. Mineral and bone disorder starts early in CKD and affects the incidence of bone fractures. The aim of this study was to observe the frequency of diverse bone fractures in patients with CKD not on dialysis. METHODS: This cohort study included 68 patients that were followed during the two-year period. The patients were divided into two cohorts: one that developed bone fractures and the other that did not. There were 35 (51.5%) men and 33 (48.5%) women. The mean age of patients ranged 62.88±11.60 years. During follow-up serum values of chronic kidney disease - mineral and bone indicators were measured. The methods of descriptive and analytical statistics were used in order to analyze obtained data. RESULTS: During this two-year follow-up seven patients developed bone fractures. Among them, females dominated (6 patients) compared to males (only 1 patient). The most common were fractures of forearm. The mean level of parathyroid hormone (PTH) at the beginning of the monitoring was higher in the group of patients with bone fractures (165.25 ± 47.69 pg/mL) in regard to another group (103.96 ± 81.55 pg/mL). After two-year follow-up, this difference became statistically significant at the level p < 0.05. Patients that developed bone fractures had higher FRAX (Fracture Risk Assessment) score compared to another group. CONCLUSION: In our study, about 10% of patients had bone fractures in the two-year follow-up period. Patients who developed fractures had a higher PTH level and FRAX score.