Cardiovascular biomarkers in chronic kidney disease

Przewlekła choroba nerek (CKD) jest istotnym problemem zdrowia publicznego na całym świecie. Wysoka zachorowalność na choroby układu sercowo-naczyniowego (CVD) i wysoka śmiertelność pacjentów ze współistniejącą CKD, szczególnie w jej zaawansowanych stadiach, uzasadniają potrzebę stratyfikacji ryzyka sercowo-naczyniowego w tej populacji chorych. Znane czynniki ryzyka, takie jak przewlekły stan zapalny, stres oksydacyjny, niedokrwistość czy zaburzenia mineralne i kostne, w znacznym stopniu przyczyniają się do dużej częstości występowania powikłań sercowo-naczyniowych u chorych z CKD. Biomarkery metaboliczne związane z tymi czynnikami ryzyka mogą mieć istotne znaczenie w przewidywaniu rozwoju CVD. Precyzyjna ocena ryzyka sercowo-naczyniowego na wczesnym etapie mogłaby ułatwić podjęcie decyzji o agresywnym postępowaniu u wybranych pacjentów w celu zmniejszenia częstości powikłań. W artykule omówiono epidemiologię CKD i CVD, mechanizmy zwapnienia naczyń, jak również możliwości wykorzystania biomarkerów w ocenie ryzyka sercowo-naczyniowego u pacjentów z CKD.  Chronic kidney disease (CKD) is a growing public health problem worldwide. The high incidence of cardiovascular diseases (CVD) and high mortality rates in patients with CKD, particularly in advanced stages, bring a rationale for better risk stratification in this population. Known risk factors such as inflammation, oxidative stress, anemia, and bone mineral disorders contribute by large to the high incidence of cardiovascular complications diagnosed in patients with CKD. Metabolic biomarkers related to these events might be valuable in predicting CVD. The accurate assessment of cardiovascular risk at an early stage could facilitate more aggressive and better tailored treatment of selected patients in order to reduce event rates. In this review, we discuss the epidemiology of CKD and CVD, the mechanisms of vascular calcification, as well as established and emerging laboratory biomarkers for the cardiovascular risk assessment in CKD

URINARY PROTEOMIC MARKERS OF IGA NEPHROPATHY, LUPUS NEPHRITIS AND MEMBRANOUS NEPHROPATHY

INTRODUCTION: Chronic kidney disease (CKD) is a worldwide public health problem, related to increased morbidity and mortality. Glomerulopathies represent major causes of CKD and require complicated diagnostics. Standard of care includes kidney biopsy in order to confirm the type of nephropathy. However, biopsy brings specific risks. Therefore, non-invasive diagnostic and prognostic methods are sought. Urinary proteomics emerged as safe and promising tool, but still requires development and improvements. Our previous studies which are part of European Patent Application from 10th June 2016 (WO/2017/212463), identified urinary markers of IgA nephropathy. They included among others: alpha-1B-glycoprotein (A1BG), alpha-l-acid glycoprotein 1 (ORM-1), ferritin light chain (FTL) and serotransferrin (TF). The aim of this study was to evaluate them in comparison to patients with glomerulopathies of different etiologies, such as lupus nephritis (LN) and membranous nephropathy (MN). METHODS: This proteomic study included patients with CKD (41 IgAN, 33 LN, 26 MN, 6 with erytrocyturia of unknown etiology) and 19 healthy controls. Urine samples were obtained from a midstream of the: first-morning (FM) and second- or third-morning (SPOT) sample. The SPOT samples were processed up to 2 h and FM samples up to 4 h after collection, by agitating and gently inverting 4-6 times, portioned into 2-ml aliquots and stored at -80°C for further measurements. Western Blotting was used for analysis of the SPOT and FM samples, ELISA and mass spectrometry for SPOT urine only. The results were related to demographic data, standard laboratory tests and GFR estimated with use of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. RESULTS: The urinary concentrations of A1BG, ORM-1, FTL and TF were found to be higher in CKD patients than in healthy controls. Moreover, these proteins varied depending on the disease. According to ELISA measurements, patients with IgAN, erytrocyturia and LN had significantly more A1BG and ORM-1 (p < 0.05), whereas TF was more elevated in LN and MN individuals comparing to healthy controls. The western blot analysis revealed significantly elevated level of A1BG, ORM-1 and FTL in IgAN, LN and MN, comparing to healthy control. Additionally, it revealed fragmentation of A1BG in several patients and the bottom range bands tended to be most prominently elevated in IgAN patients. Mass spectrometry confirmed differences between the diseases according to the specific amino acids fragments of each tested protein. Figure 1. Western blot scans for urinary A1BG, ORM-1 and FTL in CKD patients (2-4) and healthy controls (1). CONCLUSIONS: The urinary concentrations of A1BG, ORM-1, FTL and TF are elevated in CKD patients and vary depending on the type of nephropathy. This observation suggests their differential roles in the pathophysiology of the given diseases, and we believe their evaluation may help distinguishing between nephropathies. Further studies are desired to establish the role of these urinary proteins in non-invasive disease differentiation

Rapamycin and the transcription factor C/EBPβ as a switch in osteoclast differentiation: implications for lytic bone diseases

Lytic bone diseases and in particular osteoporosis are common age-related diseases characterized by enhanced bone fragility due to loss of bone density. Increasingly, osteoporosis poses a major global health-care problem due to the growth of the elderly population. Recently, it was found that the gene regulatory transcription factor CCAAT/enhancer binding protein beta (C/EBPβ) is involved in bone metabolism. C/EBPβ occurs as different protein isoforms of variable amino terminal length, and regulation of the C/EBPβ isoform ratio balance was found to represent an important factor in osteoclast differentiation and bone homeostasis. Interestingly, adjustment of the C/EBPβ isoform ratio by the process of translational control is downstream of the mammalian target of rapamycin kinase (mTOR), a sensor of the nutritional status and a target of immunosuppressive and anticancer drugs. The findings imply that modulating the process of translational control of C/EBPβ isoform expression could represent a novel therapeutic approach in osteolytic bone diseases, including cancer and infection-induced bone loss

On the Action of Cyclosporine A, Rapamycin and Tacrolimus on M. avium Including Subspecies paratuberculosis

BACKGROUND: Mycobacterium avium subspecies paratuberculosis (MAP) may be zoonotic. Recently the "immuno-modulators" methotrexate, azathioprine and 6-MP and the "anti-inflammatory" 5-ASA have been shown to inhibit MAP growth in vitro. We concluded that their most plausible mechanism of action is as antiMAP antibiotics. The "immunosuppressants" Cyclosporine A, Rapamycin and Tacrolimus (FK 506) treat a variety of "autoimmune" and "inflammatory" diseases. Rapamycin and Tacrolimus are macrolides. We hypothesized that their mode of action may simply be to inhibit MAP growth. METHODOLOGY: The effect on radiometric MAP (14)CO(2) growth kinetics of Cyclosporine A, Rapamycin and Tacrolimus on MAP cultured from humans (Dominic & UCF 4) or ruminants (ATCC 19698 & 303) and M. avium subspecies avium (ATCC 25291 & 101) are presented as "percent decrease in cumulative GI" (%-DeltacGI.) PRINCIPAL FINDINGS: The positive control clofazimine has 99%-DeltacGI at 0.5 microg/ml (Dominic). Phthalimide, a negative control has no dose dependent inhibition on any strain. Against MAP there is dose dependent inhibition by the immunosuppressants. Cyclosporine has 97%-DeltacGI by 32 microg/ml (Dominic), Rapamycin has 74%-DeltacGI by 64 microg/ml (UCF 4) and Tacrolimus 43%-DeltacGI by 64 microg/ml (UCF 4) CONCLUSIONS: We show heretofore-undescribed inhibition of MAP growth in vitro by "immunosuppressants;" the cyclic undecapeptide Cyclosporine A, and the macrolides Rapamycin and Tacrolimus. These data are compatible with our thesis that, unknowingly, the medical profession has been treating MAP infections since 1942 when 5-ASA and subsequently azathioprine, 6-MP and methotrexate were introduced in the therapy of some "autoimmune" and "inflammatory" diseases

The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis

Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 × 10-12) and IRF4 (rs9405192, OR = 1.29, P = 1.4 × 10-14), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 × 10-103) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10-49), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10-93), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10-23 and OR = 3.39, P = 5.2 × 10-82, respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk

The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis

Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 × 10-12) and IRF4 (rs9405192, OR = 1.29, P = 1.4 × 10-14), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 × 10-103) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10-49), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10-93), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10-23 and OR = 3.39, P = 5.2 × 10-82, respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk

Lupus Nephritis and Dysbiosis

Lupus nephritis (LN) is one of the most common and serious complications of systemic lupus erythematosus (SLE). The risk factors for developing LN by SLE patients are not fully understood. They are considered to be a mix of genetic and environmental variables, one of them being dysbiosis, proposed recently to interfere with autoimmunity. As of yet, the relations between the human microbiome, its genetic determinants, individual variability and clinical consequences remain to be established. One of the major obstacles in studying them is the magnitude of confounders, such as diet, drugs, infections or antibiotics use. They also make comparison between the studies extremely complicated. We reviewed the available evidence for the interplay between microbiome, dysbiosis and mechanisms triggering the autoimmune responses and potentially contributing to LN development. One such mechanism is the stimulation of autoimmune responses by bacterial metabolites that can mimic autoantigens and cause antibody production. These mimicking microbial antigens seem to be a promising target for future interventions

Selected novel aspects in pathogenesis of lupus erythematosus – interdisciplinary view

Lupus erythematosus is an autoimmune disease characterized by complex immune disturbances concerning humoral and cell-mediated immune responses. Despite intensive research, many pathological processes regarding this disorder remain unexplained. During interdisciplinary investigations on the etiology of lupus and its complications special interest has recently been referred to heat-shock proteins, antibodies directed against such proteins and galectin-3. These issues are extensively studied not only by dermatologists and rheumatologists, but also by cardiologists (in terms of cardiovascular complications) and nephrologists (in terms of lupus nephritis). This study presents the current state of dermatological, nephrological and cardiological knowledge on this topic

The Different Patterns of Over-the-Counter Nonsteroidal Anti-Inflammatory Drugs or Analgesics Use in Patients with Chronic Kidney Disease and the General Population

Nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics are the most commonly used drugs worldwide and their availability over-the-counter is increasing. The aim of this study was to examine the frequency of their use as well as the awareness of the associated risk of side effects in patients with chronic kidney disease (CKD) compared to the patients at general practice (GP) offices. We found that 88.5% of the CKD and 97.1% of the GP group used NSAIDs and/or analgesics (p &lt; 0.0001). Paracetamol was chosen the most often by both study groups, but the proportion of patients taking paracetamol was significantly higher in the CKD group (p &lt; 0.006). On the contrary, the proportion of patients taking ibuprofen was significantly higher in GP group (p &lt; 0.0001). Furthermore, almost 37% of CKD and 60% of GP patients never consult with their doctor before taking NSAIDs or analgesics. The influence of advertisements on the decision to take these drugs was found to be marginal in both groups. In conclusion, the NSAIDs and/or analgesics use is very common. The differences between the studied cohorts in self-decision making and the type of drugs used between the studied cohorts warrant tailored educational approaches