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

Glucocorticosteroid-free versus glucocorticosteroid-containing immunosuppression for liver transplanted patients

BACKGROUND: Liver transplantation is an established treatment option for end-stage liver failure. Now that newer, more potent immunosuppressants have been developed, glucocorticosteroids may no longer be needed and their removal may prevent adverse effects.OBJECTIVES: To assess the benefits and harms of glucocorticosteroid avoidance (excluding intra-operative use) or withdrawal versus glucocorticosteroid-containing immunosuppression following liver transplantation.SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index Expanded and Social Sciences Citation Index, The Transplant Library, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) until September 2014.SELECTION CRITERIA: Randomised clinical trials assessing glucocorticosteroid avoidance or withdrawal versus glucocorticosteroid-containing immunosuppression for liver-transplanted people. Our inclusion criteria stated that participants should have received the same co-interventions. We included trials that assessed complete glucocorticosteroid avoidance (excluding the perioperative period and excluding the occurrence of acute rejection) versus short-term glucocorticosteroids, as well as trials that assessed short-term glucocorticosteroids versus long-term glucocorticosteroids.DATA COLLECTION AND ANALYSIS: We used RevMan to conduct meta-analyses, calculating risk ratio (RR) for dichotomous variables and mean difference (MD) for continuous variables, both with 95% confidence intervals (CIs). We used a random-effects model and a fixed-effect model and reported both results where a discrepancy existed. We assessed the risk of systematic errors using risk of bias domains. We controlled for random errors by performing Trial Sequential Analysis. We presented our results in a 'Summary of findings' table.MAIN RESULTS: We included 16 completed randomised clinical trials with a total of 1347 participants. We found 10 trials that assessed complete postoperative glucocorticosteroid avoidance (excluding intra-operative use and treatment of rejection) versus short-term glucocorticosteroids (782 participants) and six trials that assessed short-term glucocorticosteroids versus long-term glucocorticosteroids (565 participants). We found one ongoing trial assessing complete postoperative glucocorticosteroid avoidance versus short-term glucocorticosteroids, which is expected to enrol 300 participants. All trials were at high risk of bias. Overall, we found no statistically significant difference for mortality (RR 1.15, 95% CI 0.93 to 1.44; low-quality evidence), graft loss including death (RR 1.16, 95% CI 0.91 to 1.48; low-quality evidence), or infection (RR 0.88, 95% CI 0.73 to 1.05; low-quality evidence) when glucocorticosteroid avoidance or withdrawal was compared with glucocorticosteroid-containing immunosuppression. Acute rejection and glucocorticosteroid-resistant rejection were statistically significantly more frequent when glucocorticosteroid avoidance or withdrawal was compared with glucocorticosteroid-containing immunosuppression (RR 1.33, 95% CI 1.08 to 1.64; moderate-quality evidence; and RR 2.14, 95% CI 1.13 to 4.02; very low-quality evidence). Diabetes mellitus and hypertension were statistically significantly less frequent when glucocorticosteroid avoidance or withdrawal was compared with glucocorticosteroid-containing immunosuppression (RR 0.81, 95% CI 0.66 to 0.99; low-quality evidence; and RR 0.76, 95% CI 0.65 to 0.90; low-quality evidence). We performed Trial Sequential Analysis for all outcomes. None of the outcomes crossed the monitoring boundaries or reached the required information size. Hence, we cannot exclude random errors from the results of the conventional meta-analyses.AUTHORS' CONCLUSIONS: Many of the benefits and harms of glucocorticosteroid avoidance or withdrawal remain uncertain because of the limited number of published randomised clinical trials, limited numbers of participants and outcomes, and high risk of bias in the trials. Glucocorticosteroid avoidance or withdrawal appears to reduce diabetes mellitus and hypertension whilst increasing acute rejection, glucocorticosteroid-resistant rejection, and renal impairment. We could identify no other benefits or harms of glucocorticosteroid avoidance or withdrawal. Glucocorticosteroid avoidance or withdrawal may be of benefit in selected patients, especially those at low risk of rejection and high risk of hypertension or diabetes mellitus. The optimal duration of glucocorticosteroid administration remains unclear. More randomised clinical trials assessing glucocorticosteroid avoidance or withdrawal are needed. These should be large, high-quality trials that minimise the risk of random and systematic error.</p

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