Cardiorenal Syndrome Type 4—Cardiovascular Disease in Patients with Chronic Kidney Disease: Epidemiology, Pathogenesis, and Management

The term cardiorenal syndrome refers to the interaction between the heart and the kidney in disease and encompasses five distinct types according to the initial site affected and the acute or chronic nature of the injury. Type 4, or chronic renocardiac syndrome, involves the features of chronic renal disease (CKD) leading to cardiovascular injury. There is sufficient epidemiologic evidence linking CKD with increased cardiovascular morbidity and mortality. The underlying pathophysiology goes beyond the highly prevalent traditional cardiovascular risk burden affecting renal patients. It involves CKD-related factors, which lead to cardiac and vascular pathology, mainly left ventricular hypertrophy, myocardial fibrosis, and vascular calcification. Risk management should consider both traditional and CKD-related factors, while therapeutic interventions, apart from appearing underutilized, still await further confirmation from large trials

FGF-23 Levels before and after Renal Transplantation

Phosphatonin fibroblast growth factor-23 (FGF-23) is involved in phosphate (P) excretion and vitamin D metabolism. Recently, FGF-23 has been suggested to be responsible for the hypophosphatemia and inappropriately low calcitriol levels observed after renal transplantation. We performed a prospective study to investigate FGF-23 levels in patients with end-stage renal disease before and after renal transplantation and their probable association with markers of bone and mineral metabolism. Intact FGF-23 levels were determined before and at 3, 6, and 12 months posttransplantation in 18 renal transplant recipients. Intact parathyroid hormone (iPTH), calcium (Ca), P, 25(OH)VitD, and 1,25(OH)2VitD levels were measured at the same time periods. Renal threshold phosphate concentration (TmPO4/GFR) was also calculated at 3, 6, and 12 months posttransplantation. The results showed that FGF-23 levels decreased by 89% 3 months posttransplantation (346 ± 146 versus 37 ± 9 pg/mL, P < .01) and remained stable throughout the study period. iPTH and P levels also decreased significantly after renal transplantation, while Ca and 1,25(OH)2VitD increased. Pretransplantation FGF-23 was significantly correlated with P levels at 3 months posttransplantation (P < .005). In conclusion, FGF-23 levels decrease dramatically after successful renal transplantation. Pre-transplantation FGF-23 correlate with P levels 3 months posttransplantation

Clinical Study FGF-23 Levels before and after Renal Transplantation

Recommended by Bruce Kaplan Phosphatonin fibroblast growth factor-23 (FGF-23) is involved in phosphate (P) excretion and vitamin D metabolism. Recently, FGF-23 has been suggested to be responsible for the hypophosphatemia and inappropriately low calcitriol levels observed after renal transplantation. We performed a prospective study to investigate FGF-23 levels in patients with end-stage renal disease before and after renal transplantation and their probable association with markers of bone and mineral metabolism. Intact FGF-23 levels were determined before and at 3, 6, and 12 months posttransplantation in 18 renal transplant recipients. Intact parathyroid hormone (iPTH), calcium (Ca), P, 25(OH)VitD, and 1,25(OH) 2 VitD levels were measured at the same time periods. Renal threshold phosphate concentration (TmPO 4 /GFR) was also calculated at 3, 6, and 12 months posttransplantation. The results showed that FGF-23 levels decreased by 89% 3 months posttransplantation (346 ± 146 versus 37 ± 9 pg/mL, P &lt; .01) and remained stable throughout the study period. iPTH and P levels also decreased significantly after renal transplantation, while Ca and 1,25(OH) 2 VitD increased. Pretransplantation FGF-23 was significantly correlated with P levels at 3 months posttransplantation (P &lt; .005). In conclusion, FGF-23 levels decrease dramatically after successful renal transplantation. Pre-transplantation FGF-23 correlate with P levels 3 months posttransplantation

CD20+ B Cell Depletion in Systemic Autoimmune Diseases: Common Mechanism of Inhibition or Disease-Specific Effect on Humoral Immunity?

Autoimmunity remains a complex physiologic deviation, enabled and perpetuated by a variety of interplayers and pathways. Simplistic approaches, targeting either isolated end-effectors of more centrally placed interactors of these mechanisms, are continuously tried in an effort to comprehend and halt cascades with potential disabling and deleterious effects in the affected individuals. This review focuses on theoretical and clinically proved effects of rituximab-induced CD20+ B cell depletion on different systemic autoimmune diseases and extrapolates on pathogenetic mechanisms that may account for different interindividual or interdisease responses

A study on the pathogenesis of vascular alterations and bone metabolism disorders in patients with end stage renal disease

The aim of the present study was to investigate the association between serum levels of the calcification inhibitor fetuin-A, the osteoclast inhibitor osteoprotegerin and the phosphatonin FGF-23, with arterial stiffness and with early atherosclerosis, in hemodialysis patients. The study enrolled 81stable chronic hemodialysis patients. Serum levels of fetuin-A, osteoprotegerin, intact FGF-23 (iFGF-23) and c-terminal FGF-23 (cFGF-23) were measured by enzyme-linked immunosorbent assay. Vascular stiffness was evaluated by measuring the carotid to femoral pulse wave velocity (PWV) with applanation tonometry and simultaneous electrocardiography. Early atherosclerosis was evaluated by measuring the common carotid intima-media thickness (IMT), which was visualized bilaterally by B-mode ultrasonography, in the far vessel wall at three points central to the carotid bulb. In univariate analysis PWV was positively associated with age (p=0,000), co-morbidities like diabetes mellitus (p=0,039), hypertension (p=0,024), cardiovascular disease (p=0,003) and coronary heart disease (p=0,016). There was also a positive association with SAP (p=0,006), PP (p=0,006), and LDL levels (p=0,037). PWV was negatively associated with fetuin-A (p=0,001), and positively with osteoprotegerin (p=0,000), while there was no linear correlation with either cFGF-23 or iFGF-23 levels. In multiple regression analysis both fetuin-A and osteoprotegerin displayed an independent association with PWV (p=0,032, standard beta=-0197 and p=0,041, standard beta=0,227 respectively). In a subgroup of patients without coronary heart disease (n=59) PWV values lower than 9,1m/sec and higher than 11,1m/sec were positively associated with iFGF-23 levels (p=0,032). In multiple regression this association was independent of age, diabetes, pulse pressure and levels of fetuin-A and osteoprotegerin (p=0.049). In univariate analysis IMT was positively associated with age (p=0,000), co-morbidities like diabetes, (p=0,005), cardiovascular disease (p=0,001) and coronary heart disease (p=0,001).There was a negative association with DAP (p=0,008) and MAP (p=0,032), as well as with six month average albumin levels (p=0,008), and a positive association with logCRP (p=0,01). Regarding the factors under investigation IMT was negatively associated with fetuin-A (p=0,005) and positively with osteoprotegerin (p=0,000). However, these associations were confounded by age. IMT did not show a linear correlation either with cFGF-23 or iFGF-23 levels. Nevertheless higher than the average iFGF-23 levels were associated with higher IMT values (p=0,035) and this was independent of age. In multiple regression analysis IMT was independently associated with age (p=0,000, standard beta=0,570), cardiovascular disease (p=0,031, standard beta=0,166), and higher than the mean iFGF-23 levels (p=0,028, standard beta=0,164). In a model including only the serum markers associated with IMT an independent association was displayed with osteoprotegerin (p=0,000, standard beta=0,420), iFGF-23 levels (p=0,016, standard beta=0,232) and fetuin-Α (p=0,032, standard beta=-0,223). In conclusion, in chronic hemodialysis patients arterial stiffness (PWV) exhibited a negative independent correlation with fetuin-A and a positive with osteoprotegerin. The negative association of fetuin-A and the positive of osteoprotegerin with early atherosclerosis (IMT) was confounded by age.Σκοπός της παρούσας μελέτης ήταν η διερεύνηση σε αιμοκαθαιρόμενους ασθενείς της συσχέτισης των επιπέδων στον ορό της φετουΐνης-Α, της οστεοπροτεγερίνης και του FGF-23, με τη σκλήρυνση του αρτηριακού τοιχώματος και την αρχόμενη αθηροσκλήρωση.Στη μελέτη εντάχθηκαν 81 ασθενείς υπό χρόνια αιμοκάθαρση. Τα επίπεδα φετουΐνης-Α, οστεοπροτεγερίνης, άθικτου μορίου FGF-23 (iFGF-23) και καρβοξυτελικού τμήματος (cFGF-23) προσδιορίστηκαν στον ορό με ανοσοενζυμική μέθοδο. Η σκλήρυνση του αρτηριακού τοιχώματος εκτιμήθηκε με τη μέτρηση της ταχύτητας αγωγής σφυγμικού κύματος (PWV) μεταξύ καρωτίδας και μηριαίας αρτηρίας. Η αρχόμενη αθηροσκλήρωση εκτιμήθηκε με την υπερηχογραφική μέτρηση του πάχους του έσω-μέσου χιτώνα (ΙΜΤ) της κοινής καρωτίδας. Η PWV παρουσίασε αρνητική συσχέτιση με την φετουΐνη-Α (p=0,001), και θετική με την οστεοπροτεγερίνη (p=0,000), ενώ δεν παρουσίασε γραμμική συσχέτιση με τα επίπεδα cFGF-23 και iFGF-23. Σε μοντέλο πολλαπλής γραμμικής παλινδρόμησης, τόσο η φετουΐνη-Α όσο και η οστεοπροτεγερίνη παρουσίασαν ανεξάρτητη συσχέτιση με την PWV (p=0,032, standard beta=-0197 και p=0,041, standard beta=0,227 αντίστοιχα). Σε υποομάδα 59 ασθενών χωρίς στεφανιαία νόσο ταχύτητες αγωγής σφυγμικού κύματος 11,1m/sec παρουσίασαν θετική συσχέτιση με τα επίπεδα iFGF-23 (p=0,032), η οποία στην πολυπαραγοντική ανάλυση ήταν ανεξάρτητη από την ηλικία, την παρουσία σακχαρώδους διαβήτου, την πίεση σφυγμού και τα επίπεδα φετουΐνης-Α, οστεοπροτεγερίνης (p=0.049). Στη μονοπαραγοντική ανάλυση το ΙΜΤ παρουσίασε αρνητική συσχέτιση με την φετουΐνη-Α (p=0,005), και θετική με την οστεοπροτεγερίνη (p=0,000). Οι συσχετίσεις όμως αυτές δεν ήταν ανεξάρτητες από την ηλικία. Το ΙΜΤ δεν παρουσίασε γραμμική συσχέτιση με τα επίπεδα cFGF-23 και iFGF-23. Όμως υψηλότερα από το μέσο όρο επίπεδα iFGF-23 συσχετίσθηκαν με υψηλότερες τιμές ΙΜΤ (p=0,035). Η συσχέτιση αυτή ήταν ανεξάρτητη από την ηλικία. Στην πολυπαραγοντική ανάλυση ανεξάρτητη συσχέτιση με το ΙΜΤ παρουσίασαν η ηλικία (p=0,000, standard beta=0,570), η παρουσία καρδιαγγειακής νόσου (p=0,031, standard beta=0,166), και τα υψηλότερα σε σχέση με το μέσο όρο επίπεδα iFGF-23 (p=0,028, standard beta=0,164). Σε μοντέλο που περιελάμβανε μόνο τους ορολογικούς δείκτες που συσχετίσθηκαν με το ΙΜΤ ανεξάρτητη συσχέτιση με το ΙΜΤ παρουσίασαν η οστεοπροτεγερίνη (p=0.000, standard beta=0,420), τα επίπεδα iFGF-23 (p=0.016, standard beta=0,232) και η φετουΐνη-Α (p=0.032, standard beta=-0,223). Συμπερασματικά σε ασθενείς υπό χρόνια αιμοκάθαρση η φετουΐνη-Α και η οστεοπροτεγερίνη παρουσίασαν ανεξάρτητη γραμμική συσχέτιση, αρνητική και θετική αντίστοιχα, με τη σκλήρυνση του αρτηριακού τοιχώματος, ως ταχύτητα αγωγής σφυγμικού κύματος (PWV). Η συσχέτισή τους με την αρχόμενη αθηροσκλήρωση ως πάχυνση του αρτηριακού τοιχώματος (IMT) δεν ήταν ανεξάρτητη από την ηλικία

Targeting the B-Cell Pathway in Lupus Nephritis: Current Evidence and Future Perspectives

Nephritis represents a frequent, severe complication of systemic lupus erythematosus. Autoantibodies appear to be fundamental in the pathogenesis of lupus nephritis. Several hypotheses are currently experimentally tested to further elucidate the direct induction of inflammation through interaction of the pathological autoantibodies with intrinsic glomerular components and the triggering of a complement-driven autoinflammatory cascade. B-cells have, in the last decade, emerged as a promising new therapeutic target, as biological treatments successfully attempting B-cell depletion, inhibition of B-cell proliferation and differentiation, or modulation of B-cell function have become bioengineered. Clinical trials have so far proved controversial regarding the efficacy of these new agents. Thus, despite the short and long-term side effects associated with immunosuppressive treatment alternative emerging treatments are still regarded “rescue” regimens in refractory patients. In an effort to accurately evaluate the potential of these therapies in lupus nephritis, several issues have been raised mainly in terms of patient selection criteria and trial duration. This review aims to expand on the proposed pathophysiologic mechanisms implicating the B-cell pathway in the pathogenesis of lupus nephritis and summarize current knowledge obtained from clinical trials introducing these biologics in its treatment. Finally, it will elaborate on potential applications of currently available biologic agents and forthcoming treatment options

Pregnancy in Systemic Lupus Erythematosus Patients with Nephritis

Pregnancy in patients with lupus nephritis is a challenging clinical situation. Although not absolutely contraindicated, it is associated with increased risk for foetal and maternal complications, including foetal loss, preterm delivery, intrauterine growth retardation, hypertension, pre-eclampsia, nephritis flare, and, rarely, maternal death. The complication rate is further increased in the presence of antiphospholipid antibodies or the antiphospholipid syndrome. Proliferative classes of nephritis (III and IV) also appear to confer excess risk for complications. Immunosuppressives such as cyclophosphamide and mycophenolate, and antihypertensives such as angiotensin-converting-enzyme (ACE) inhibitors and angiotensin receptor blockers need to be stopped due to teratogenic effects. Agents like corticosteroids, azathioprine, and probably calcineurin inhibitors are considered compatible with gestation. Lupus activity needs to be assessed and carefully monitored. Thrombotic risk due to antiphospholipid antibodies, thrombotic events, or nephrosis needs to be evaluated and managed accordingly, with the use of aspirin and/or unfractioned or low molecular weight heparin. Differentiating between severe pre-eclampsia and lupus nephritis flare might require a renal biopsy, which might not always be feasible, for example after the 32nd gestational week or in a setting of uncontrolled hypertension or thrombocytopaenia. A 6-month history of quiescent disease on non-teratogenic agents seems to be associated with best chance for favourable outcomes. Pregnancy is optimally managed by a multidisciplinary team of experienced specialists, and close monitoring for disease activity during gestation; additionally, follow-up for maternal flare postpartum is also advised

Diagnosing and Treating IgAN: Steroids, Budesonide, or Maybe Both?

IgA nephropathy (IgAN), the most common primary glomerulonephritis worldwide, is characterized by a mesangial IgA deposit and a variety of histological lesions, as described by the Oxford classification system. Despite the well-described “four-hit hypothesis”, there are still plenty of less or undescribed mechanisms that participate in the disease pathogenesis, such as B-cell priming, which seems to be initiated by different antigens in the intestinal microbiota. Diagnosis of the disease is currently based on kidney biopsy findings, as the sensitivity and specificity of the many serum and urinary biomarkers described so far do not seem to have diagnostic accuracy. Therapeutic strategies consist of the initial step of non-immune medication, aiming to reduce both the intraglomerular pressure and proteinuria to below 0.5 g/day, followed by systemic corticosteroid administration in patients who remain at high risk for progressive chronic kidney disease despite the maximum non-immune treatment. The 6-month systemic corticosteroid treatment reduces proteinuria levels; however, the increased possibility of adverse events and increased relapse rate after treatment raises the need for a new therapeutic approach. Targeted-release budesonide is a therapeutic modality that aims to inhibit disease pathogenetic pathways at early stages; it has minor systemic absorption and proven beneficial effects on renal function and proteinuria. In the present systemic review, the benefits and adverse events of steroids and budesonide are described, and the possibility of combined treatment is questioned in selected cases with active histologic lesions