ABSTRACT
BACKGROUND: Fabry disease (FD) is a rare lysosomal storage disease causing progressive loss of target organ function. All renal cell types are involved from the early stages, even before clinical signs can be detected. FD-specific therapies can stop/mitigate disease progression. Thus, it is important to validate early markers of renal lesions so that they can be adopted as criteria for timely treatment initiation. MATERIALS AND METHODS: We retrospectively analyzed and extensively evaluated 21 FD case patients; this evaluation included a kidney biopsy. We looked for the influence of pathological findings on the management of FD patients. In addition, we investigated the association between general and FD-specific features and long-term patients' outcomes. We defined a combined endpoint as being at least one of the following: 50% decrease of estimated glomerular filtration rate (eGFR) from baseline, kidney failure (KF), end-stage kidney disease (ESKD), or death and mortality. RESULTS: Our cohort of 21 FD patients (11 males and 10 females) was stratified according to the presence of the combined endpoint: group 1 (n = 15) included patients without the combined endpoint, while group 2 (n = 6) patients reached the combined endpoint outcome. Patients from group 2 presented lower mean baseline eGFR (72.2 ± 38.7 mL/min/1.73 m2 vs. 82.5 ± 26.4 mL/min/1.73 m2) without statistical significance (p = 0.44), but significantly (p = 0.22) higher median baseline proteinuria (2.7 g/24 h vs. 0.4 g/24 h). Specific lysosomal deposits were identified in all patients. Segmental sclerosis was present in all patients with the combined endpoint and in only 33% of patients without the combined endpoint (p = 0.009). Global sclerosis and interstitial fibrosis were present in both groups, with no significant differences. A total of 15 out of the 16 treatment-naïve patients (7 males and 9 females) started FD-specific therapy after kidney biopsy. Treatment was initiated in all male FD patients and in 8 female patients. In 2 females, pathological findings in kidney biopsy offered important reasons to start FD treatment, although specific criteria of the Romanian protocol for prescription of FD-specific therapy were still not fulfilled. Cox univariate analysis showed that every increase in 24 h proteinuria with 1 g is associated with a 65% risk of developing the combined endpoint (HR = 1.65; 95%CI: 1.05-2.58; p = 0.02), and that the presence of segmental sclerosis increased the risk of developing the combined endpoint by 51.3 times (HR = 51.3; 95% CI: 95% CI: 1.67-103.5; p = 0.01). Kaplan-Meier analysis showed that the cumulative risk of developing the combined endpoint was higher in patients in whom segmental sclerosis (100% vs. 0%, log-rank test, p = 0.03) was present. CONCLUSIONS: Histological evaluation is an important tool for the detection of early kidney involvement and provides additional support to the early initiation of FD-specific therapy. Presence of segmental sclerosis can predict the long-term outcomes of kidney disease deterioration and mortality and may be used as an early indicator of disease progression. Additionally, in the absence of other criteria according to current guidelines, specific FD renal lesions as revealed by kidney biopsy might become a distinct criterion to initiate FD therapy.
ABSTRACT
Chronic kidney disease (CKD) is an irreversible loss of kidney function, and it represents a major global public health burden due to both its prevalence and its continuously increasing incidence. Mineral bone disorders (MBDs) constitute a hallmark of CKD, and alongside cardiovascular complications, they underlie a poor prognosis for these patients. Thus, our study focused on novel CKD biomarker patterns and their impact on the clinical staging of the disease. As a first testing approach, the relative expression levels of 105 proteins were assessed by the Proteome Profiler Cytokine Array Kit for pooled CKD stage 2-4 serum samples to establish an overall view regarding the proteins involved in CKD pathogenesis. Among the molecules that displayed significant dysregulation in the CKD stages, we further explored the involvement of Dickkopf-related protein 1 (Dkk-1), a recognised inhibitor of the Wnt signalling pathway, and its crosstalk with 1,25OH2D3 (calcitriol) as new players in renal bone and vascular disease. The serum levels of these two molecules were quantified by an ELISA (76 samples), and the results reveal decreasing circulating levels of Dkk-1 and calcitriol in advanced CKD stages, with their circulating expression showing a downward trend as the CKD develops. In the next step, we analysed the inflammation and MBD biomarkers' expression in CKD (by xMAP array). Our results show that the molecules involved in orchestrating the inflammatory response, interleukin-6 (IL-6) and tumour necrosis factor alpha (TNFα), as well as the mineral biomarkers osteoprotegerin (OPG), osteocalcin (OC), osteopontin (OPN), and fibroblast growth factor 23 (FGF-23), correlate with Dkk-1 and calcitriol, raising the possibility of them being potential useful CKD biomarkers. These results reveal the impact of different biomarker patterns in CKD staging and severity, thus opening up novel approaches to be explored in CKD clinical management.
Subject(s)
Biomarkers/blood , Inflammation/pathology , Renal Insufficiency, Chronic/diagnosis , Aged , Algorithms , Bone Density , Bone Diseases/complications , Bone Diseases/diagnosis , Calcitriol/blood , Cross-Sectional Studies , Female , Fibroblast Growth Factor-23 , Fibroblast Growth Factors/blood , Humans , Intercellular Signaling Peptides and Proteins/blood , Interleukin-6/blood , Male , Middle Aged , Osteocalcin/blood , Osteopontin/blood , Osteoprotegerin/blood , Phenotype , Prognosis , Proteome , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/complications , Tumor Necrosis Factor-alpha/blood , Wnt Signaling PathwayABSTRACT
Chronic kidney disease, despite being a "silent epidemic" disease, represents one of the main causes of mortality in general population, along with cardiovascular disease, which is the leading cause of poor prognosis for these patients. The specific objective of our study was to characterize the relationship between the inflammatory status, the bone disorders markers, and kidney failure in chronic kidney disease patient stages 2-4, in order to design a novel biomarker panel that improves early disease diagnosis and therapeutic response, thus being further integrated into clinical applications. A panel of proteomic biomarkers, assessed by xMAP array, which includes mediators of inflammation (IL-6, TNF-α) and mineral and bone disorder biomarkers (OPG, OPN, OCN, FGF-23, and Fetuin-A), was found to be more relevant than a single biomarker to detect early CKD stages. The association between inflammatory cytokines and bone disorders markers, IL-6, TNF-α, OPN, OPG, and FGF-23, reflects the severity of vascular changes in CKD and predicts disease progression. Proteomic xMAP analyses shed light on a new approach to clinical evaluation for CKD staging and prognosis.
ABSTRACT
BACKGROUND AND AIMS: Sulodexide has been reported to have antiproteinuric and nephroprotective properties. We investigated the effects of long-term low-dose Sulodexide on proteinuria and renal function in patients with chronic kidney disease (CKD) caused by diabetic nephropathy (DN), hypertensive nephropathy (HN) and primary glomerulonephritis (GN). MATERIAL AND METHODS: 100 patients with CKD received low-dose Sulodexide 50 mg/day for 12 months. Treatment efficacy was evaluated as proteinuria reduction compared to baseline; response was defined as a decline in proteinuria below 0.3 g/d. Renal function evolution was assessed by eGFR variation from baseline. RESULTS: All patients presented reduction of proteinuria, with global mean value of proteinuria decrease of 0.85 +/- 1.34 g/d (p<0.0001). Patients with HN had the highest mean percentage of proteinuria reduction (73 +/- 29%) and the lowest mean time period to achieve responder status (6.6 +/- 2.4 months), compared to patients with DN (57 +/- 29%, 8 +/- 2.9 months) and GN (63 +/- 24%, 10.7 +/- 1.2 months). Renal function as mean eGFR remained stable or improved during the study; significant increase was found only in HN group (3.41 +/- 6.38 ml/min/1.73 m2, p=0.043). Multivariate regression analysis identified that responder status was significantly associated with gender, baseline eGFR, baseline proteinuria and etiology of CKD. Concomitant administration of ACEIs or/and ARBs did not influence the response to Sulodexide therapy. CONCLUSIONS: Independently of ACEIs or/and ARBs therapy, long-term low-dose Sulodexide is efficient as antiproteinuric and renoprotective therapy in patients with CKD caused by DN, GN and HN. Better response is achieved in patients with lower degree of renal dysfunction.
Subject(s)
Anticoagulants/therapeutic use , Diabetic Nephropathies/drug therapy , Glomerulonephritis/drug therapy , Glycosaminoglycans/therapeutic use , Hypertension, Renal/drug therapy , Nephritis/drug therapy , Adult , Aged , Anticoagulants/pharmacology , Female , Glomerular Filtration Rate/drug effects , Glycosaminoglycans/pharmacology , Humans , Male , Middle Aged , Prospective StudiesABSTRACT
UNLABELLED: The association of NAFLD with chronic hepatitis C (CHC) has been extensively studied but little is known about its coexistence with chronic hepatitis B (CHB). AIMS: To investigate the prevalence and determinants of steatosis and insulin resistance (IR) in CHB and its consequences on liver injury compared with CHC and NAFLD. METHODS: Patients with CHB (N=110), CHC (N=111) and NAFLD (N=136) were evaluated by biomarkers of steatosis (SteatoTest>0.38 as a surrogate for steatosis >5%), IR (HOMA-IR>2.7 as a surrogate for IR) and fibrosis (FibroTest>0.48 as a surrogate for significant fibrosis, ≥F2). RESULTS: HOMA-IR gradually increased in CHB, CHC and NAFLD: 2.3±1.8; 3±2.6 and 3.8±2.7 (p<0.001). The prevalence of steatosis >5% was 21% (CHB), 43% (CHC) and 82% (NAFLD), (p<0.001). The prevalence of fibrosis≥F2 was 10% (CHB), 42% (CHC) and 21% (NAFLD), p<0.001. In CHB, IR was related to host and not viral factors. CHB patients with steatosis had higher BMI (29±5.7kg/m(2) vs. 24±4kg/m(2), p<0.001), waist circumference (96±14cm vs. 84±11cm, p=0.001) and HOMA-IR (3.9±2.6 vs. 1.8±1.2, p<0.001) than those without steatosis. HOMA-IR independently predicted steatosis in CHB (OR=1.9, 95% CI, 1.09-3.27, p<0.05) and CHC (OR=1.38; 95% CI, 1.07-1.78, p<0.02). In CHB, metabolic risk factors and HOMA-IR were not associated with significant fibrosis. HOMA-IR was an independent predictor of fibrosis in CHC. CONCLUSIONS: Steatosis may co-exist in CHB patients but with a lower prevalence than in CHC and NAFLD. In CHB steatosis is related to host and not viral factors, and is not associated with the severity of fibrosis.
Subject(s)
Hepatitis B, Chronic/epidemiology , Hepatitis C, Chronic/epidemiology , Insulin Resistance , Non-alcoholic Fatty Liver Disease/epidemiology , Obesity/epidemiology , Adult , Aged , Alanine Transaminase/metabolism , Aspartate Aminotransferases/metabolism , Body Mass Index , Comorbidity , Female , Hepatitis B, Chronic/metabolism , Hepatitis C, Chronic/metabolism , Humans , Liver Cirrhosis , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/metabolism , Prevalence , Prospective Studies , Severity of Illness Index , Triglycerides/metabolism , Viral Load , Waist Circumference , gamma-Glutamyltransferase/metabolismABSTRACT
OBJECTIVES: Scientific literature indicates that the risk of coronary heart disease morbidity and death among peritoneal dialysis patients exceeds risk observed in non-renal patients. The aims of this study were to establish the independent predictors associated with increased risk of coronary heart disease in peritoneal dialysis patients without diabetic nephropathy. MATERIALS AND METHODS: A number of 116 end-stage renal disease patients without diabetic nephropathy undergoing peritoneal dialysis were evaluated for coronary heart disease and predictive risk factors were investigated and identified. Also intima-media thickness measurements, as an early sign of atherosclerosis, were analyzed in a subset of patients in correlation with a number of traditional and non-traditional cardiovascular risk factors. RESULTS: The study sample was found to be characterized by a high prevalence of traditional risk factors: hypertension (95.7%), dyslipidemia (93.1%) and metabolic syndrome (58.6%), but also of dialysis-related risk factors: inflammation (82.8%) and anemia (55.2%). Independent variables found to be associated in regression analysis with coronary heart disease were: age, smoking status, nephroangiosclerosis, albumin, C-reactive protein and iPTH levels. Intima-media thickness was significantly higher in patients with coronary heart disease, values greater than 0.89 mm being associated with increased risks for coronary heart disease, acute coronary syndrome and cardiovascular death. CONCLUSIONS: The prevalence of traditional cardiovascular risk factors in these peritoneal dialysis patients is extremely high, but there are also some other factors involved, especially malnutrition and inflammation. Age higher than 55 years, smoking, albumin less than 3.5 g/dl, iPTH less than 150 pg/ml and nephroangiosclerosis were associated with highest odds ratio for coronary heart disease. An increasing CRP levels was associated with an increasing gradient for coronary heart disease risk.
ABSTRACT
AIM: To evaluate the prevalence of HBV, HCV, HDV and HEV infections in populations with different categories of risk and the seroprevalence of HBV and HCV infections in subjects asking for a medical examination. METHOD: We conducted a cross-sectional, epidemiological study in 2,851 subjects from the SubCarpathian and South-Eastern Romania (including 17 counties, 34% of the country area and 42% of the population). The subjects were divided into four groups: controls (n=2,540, i.e. consecutive subjects asking for a medical examination), subjects with very low risk (students; n=44), with low risk (doctors and nurses; n=93) and with high risk for viral hepatitis (hemodialysis patients; n=174). All subjects were screened for HBsAg, antiHCV and ALT level. In populations at risk, antiHBs, HBeAg, antiHBe, antiHBc (IgG), HBV-DNA, HCV-RNA, antiHDV(IgG) and antiHEV(IgG) were also assessed. RESULTS: In controls, HBV seroprevalence was 5.59% and HCV seroprevalence 4.56%. The risk factors for HBV infection were: age, male gender and South-East region of Romania. The risk factors for HCV infection were: age, female gender, elevated ALT level and the South-East region of Romania. In the very low risk population HBV, HCV, HDV and HEV seroprevalence was: 2.27%, 0%, 0% and 12.5%, respectively. In low risk population the seroprevalence was 2.15%, 1.07%, 0% and 13.98%. In hemodialysis patients, HBV and HCV seroprevalence were 7.91%, respectively 39.26%. HCV-RNA was detectable in 20.69% cases. CONCLUSION: In the South and South-Eastern Romania the seroprevalence of viral hepatitis infections is intermediate, similar to other Romanian regions or the Balkans.
Subject(s)
Hepatitis B/epidemiology , Hepatitis C/epidemiology , Hepatitis D/epidemiology , Hepatitis E/epidemiology , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Alanine Transaminase/blood , Biomarkers/blood , Child , Child, Preschool , Cross-Sectional Studies , DNA, Viral/blood , Female , Hepacivirus/genetics , Hepacivirus/immunology , Hepatitis B/diagnosis , Hepatitis B Antibodies/blood , Hepatitis B Surface Antigens/blood , Hepatitis B e Antigens/blood , Hepatitis B virus/genetics , Hepatitis B virus/immunology , Hepatitis C/diagnosis , Hepatitis C Antibodies/blood , Hepatitis D/diagnosis , Hepatitis Delta Virus/immunology , Hepatitis E/diagnosis , Hepatitis E virus/immunology , Humans , Infant , Infant, Newborn , Male , Middle Aged , Occupational Exposure , Prevalence , RNA, Viral/blood , Renal Dialysis/adverse effects , Risk Assessment , Risk Factors , Romania/epidemiology , Seroepidemiologic Studies , Sex Factors , Young AdultABSTRACT
AIM: This is a retrospective, observational study regarding the experience of the Fundeni Clinical Institute in the application of the Molecular Adsorbents Recirculating System in patients with liver failure. METHOD: From January 2002 until December 2007, we performed 50 MARS sessions in 27 patients, mean age 38.96+/-19.58 years. The etiology of liver failure was as follows: acute liver failure (ALF) in 7 patients, acute-on-chronic liver failure (AoCLF) in 10 patients, post-liver transplantation in 8 patients, and post-hepatectomy in 2 patients. RESULTS: We noticed the following clinical effects: improvement in general condition, in neurological status, marked regression of jaundice and pruritus, improvement in renal function and in hemodynamic status. Of the 7 patients with ALF, 3 patients (42.8 %) survived due to their own liver recovery. Only 2 patients (20%) with AoCLF survived. In this group, one patient was transplanted, one patient is alive, and the mean survival of the remaining patients was 24.5+/-34.6 days. In the post-liver transplantation group, one patient was retransplanted, one patient is alive and the mean survival of the other 6 patients was 28.5+/-39.8 days. One patient with post-hepatectomy liver failure presented spontaneous liver recovery. CONCLUSION: MARS therapy was well tolerated by the patients. MARS therapy efficiently removed water soluble and albumin-bound toxins. The unfavorable prognostic factors were the association with multi organ failure and sepsis.
Subject(s)
Liver Failure/therapy , Liver, Artificial , Adult , Hepatectomy , Humans , Liver Failure, Acute/therapy , Liver Transplantation , Middle Aged , Retrospective StudiesABSTRACT
We report a case of a young woman with an extensive, recurrent deep vein thrombosis (DVT) diagnosed by CT scan and duplex ultrasound examination. All blood investigations for etiology of recurrent DVT were normal except for serum homocysteine level, which was mildly increased. No other thrombophilic factors could be found. The three main causes of hyperhomocysteinemia are genetic defects, nutritional deficiencies and insufficient elimination. In our case a genetic defect for one of the key enzymes of homocysteine metabolism was found to be the underlying cause. Oral anticoagulation and supplementation with pyridoxine, cyanocobalamine and folate was recommended. Whether therapy with B vitamins and folate can substantially reduce the recurrence of venous thromboembolic disease remains to be established.