ABSTRACT
Aims: Long noncoding RNAs (lncRNAs) play key roles in the pathophysiology of DKD involving actions of microRNAs (miRNAs). The aims of the study were to establish the involvement of selected lncRNAs in the epigenetic mechanisms of podocyte damage and tubular injury in DKD of type 2 diabetes mellitus (DM) patients in relation to a particular miRNAs profile. Methods: A total of 136 patients with type 2 DM and 25 healthy subjects were assessed in a cross-sectional study concerning urinary albumin: creatinine ratio (UACR), eGFR, biomarkers of podocyte damage (synaptopodin, podocalyxin) and of proximal tubule (PT) dysfunction (Kidney injury molecule-1-KIM-1, N-acetyl-D-glucosaminidase-NAG), urinary lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), nuclear-enriched abundant transcript 1 (NEAT1), myocardial infarction-associated transcript (MIAT), taurine-upregulated gene 1 (TUG1), urinary miRNA21, 124, 93, 29a. Results: Multivariable regression analysis showed that urinary lncMALAT1 correlated directly with urinary synaptopodin, podocalyxin, KIM-1, NAG, miRNA21, 124, UACR, and negatively with eGFR, miRNA93, 29a (p<0.0001; R2=0.727); urinary lncNEAT1 correlated directly with synaptopodin, KIM-1, NAG, miRNA21, 124, and negatively with eGFR, miRNA93, 29a (p<0.0001; R2=0.702); urinary lncMIAT correlated directly with miRNA93 and 29a, eGFR (p<0.0001; R2=0.671) and negatively with synaptopodin, KIM-1, NAG, UACR, miRNA21, 124 (p<0.0001; R2=0.654); urinary lncTUG1 correlated directly with eGFR, miRNA93, 29a, and negatively with synaptopodin, podocalyxin, NAG, miRNA21, 124 (p<0.0001; R2=0.748). Conclusions: In patients with type 2 DM lncRNAs exert either deleterious or protective functions within glomeruli and PT. LncRNAs may contribute to DKD through modulating miRNAs expression and activities. This observation holds true independently of albuminuria and DKD stage.
Subject(s)
Diabetes Mellitus, Type 2/complications , Diabetic Nephropathies/genetics , Kidney Tubules, Proximal/physiopathology , Podocytes/physiology , RNA, Long Noncoding/metabolism , Adult , Aged , Biomarkers/metabolism , Biomarkers/urine , Cross-Sectional Studies , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/physiopathology , Diabetes Mellitus, Type 2/urine , Diabetic Nephropathies/physiopathology , Diabetic Nephropathies/urine , Female , Gene Expression Regulation/physiology , Humans , Male , MicroRNAs/metabolism , Middle Aged , Protective Factors , RNA, Long Noncoding/urine , Risk Factors , Young AdultABSTRACT
Background: The association of vascular remodeling in the kidney and the brain with a particular microRNAs (miRNA) profile is not well studied.Methods: Seventy-six patients with Type 2 diabetes and 11 healthy subjects were assessed concerning urine albumin: creatinine ratio (UACR), biomarkers of podocyte injury and of proximal tubule (PT) dysfunction. MiRNA were quantified in blood and urine by a real-time PCR System. Cerebrovascular ultrasound measurements were performed in the carotid and middle cerebral arteries.Results: MiRNA21 and miRNA124 correlated positively with nephrin, podocalyxin, synaptopodin, urinary N-acetyl-D-glucosaminidase (NAG), urinary kidney-injury molecule-1 (KIM-1), UACR, and negatively with eGFR; miRNA125a, 126, 146a, 192 correlated negatively with nephrin, podocalyxin, synaptopodin, urinary NAG, urinary KIM-1, UACR, and directly with eGFR. Plasma miRNA-21 and miRNA192 correlated directly with cerebral hemodynamics parameters of atherosclerosis and arteriosclerosis. MiRNA-124, 125a, 126, 146a showed negative correlations with the same parameters.Conclusions: In Type 2 diabetes patients there is an association of vascular remodeling in the brain and the kidney with a specific miRNAs pattern. Cerebrovascular changes occur even in normoalbuminuric patients, with 'high-to-normal' levels of podocyte injury and PT dysfunction biomarkers. These phenomena may be explained by the variability of miRNA expression within the two organs in early DKD.
Subject(s)
Cerebrovascular Disorders/metabolism , Diabetes Mellitus, Type 2/metabolism , Diabetic Angiopathies/metabolism , Diabetic Nephropathies/metabolism , MicroRNAs/metabolism , Vascular Remodeling/physiology , Adult , Cerebrovascular Disorders/blood , Cerebrovascular Disorders/etiology , Cerebrovascular Disorders/urine , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/urine , Diabetic Angiopathies/blood , Diabetic Angiopathies/etiology , Diabetic Angiopathies/urine , Diabetic Nephropathies/blood , Diabetic Nephropathies/etiology , Diabetic Nephropathies/urine , Female , Humans , Kidney Tubules/physiopathology , Male , MicroRNAs/blood , MicroRNAs/urine , Middle Aged , Podocytes/pathologyABSTRACT
BACKGROUND: Diabetic nephropathy is a severe complication of Type 2 diabetes. Tubular lesions may play an important role in its early stages. The aim of our study was to determine if atorvastatin protects the podocytes and the proximal tubule in patients with Type 2 diabetes. METHODS: A total of 63 patients with Type 2 diabetes completed this 6-months prospective pilot study. They were randomized to continue rosuvastatin therapy (control group) or to be administered an equipotent dose of atorvastatin (intervention group), and were assessed regarding urinary podocytes, podocyte-associated molecules, and biomarkers of proximal tubule dysfunction. RESULTS: The patients from the intervention group presented a significant reduction in podocyturia (from 7.0 to 4.0 cells/ml, p < .05), urinary nephrin (from 1.7 to 1.3 mg/g, p < .001), urinary vascular endothelial growth factor (from 262.8 to 256.9, p < .01), urinary alpha1-microglobulin (from 10.0 to 8.3 mg/g, p < .01), urinary kidney injury molecule-1 (from 139.5 to 136.3 ng/g, p < .001), and urinary advanced glycation end-products (from 112.6 to 101.3 pg/ml, p < .001). Podocyturia correlated directly with the podocyte damage biomarkers, proximal tubule dysfunction biomarkers, albumin to creatinine ratio, and advanced glycation end-products, and inversely with the glomerular filtration rate. CONCLUSIONS: In patients with Type 2 diabetes, atorvastatin exerts favorable effects on the kidney. There is a correlation between the evolution of the podocytes and of the proximal tubule biomarkers, supporting the hypothesis that the glomerular changes parallel proximal tubule dysfunction in the early stages of diabetic nephropathy.
Subject(s)
Atorvastatin/therapeutic use , Diabetes Mellitus, Type 2/complications , Diabetic Nephropathies/drug therapy , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Podocytes/drug effects , Rosuvastatin Calcium/therapeutic use , Aged , Albuminuria/complications , Biomarkers , Female , Glomerular Filtration Rate , Glycation End Products, Advanced/urine , Humans , Kidney Tubules, Proximal/physiopathology , Male , Membrane Proteins/urine , Middle Aged , Pilot Projects , Prospective Studies , Vascular Endothelial Growth Factor A/urineABSTRACT
INTRODUCTION AND AIMS: Balkan endemic nephropathy (BEN), a regional tubulointerstitial kidney disease encountered in South-Eastern Europe, with still undefined etiology and inexorable evolution towards end stage renal disease, raises the question of the relative contribution of family and environmental factors in its etiology. In order to evaluate the intervention of these factors, markers of tubular injury have been assessed, this lesion being considered an early renal involvement in BEN. METHODS: The paper studies relatives of BEN patients currently included in dialysis programmes (for involvement of the family factor) and their neighbors (for involvement of environmental factors) and analyzes them with regard to tubular injury by means of tubular biomarkers (N-acetyl-beta-d-glucosaminidase-NAG and alpha-1-microglobulin), and albuminuria. At the same time, glomerular filtration rate (GFR) (CKD-EPI) was measured. It is considered that, in order to acquire the disease, one should have lived for 20 years in the BEN area. The relatives have been classified according to this criterion. RESULTS: More evident tubular injury was found in the neighbors of BEN patients living for more than 20 years in the endemic area, which argues in favor of environmental factors. Higher levels of urinary alpha-1-microglobulin and albumin in relatives of BEN patients who had been living for more than 20 years in the area than in relatives with a residence under 20 years, plead for the same hypothesis. GFR was lower in persons who had been living for more than 20 years in the BEN area (neighbors and relatives). CONCLUSIONS: Environmental factors could be more important in BEN than family factors.
Subject(s)
Acetylglucosaminidase/metabolism , Albuminuria , Alpha-Globulins/metabolism , Balkan Nephropathy , Kidney Failure, Chronic , Adult , Albuminuria/diagnosis , Albuminuria/etiology , Balkan Nephropathy/complications , Balkan Nephropathy/diagnosis , Balkan Nephropathy/epidemiology , Balkan Nephropathy/metabolism , Balkan Nephropathy/physiopathology , Biomarkers/metabolism , Environmental Health/methods , Environmental Health/statistics & numerical data , Family Health/statistics & numerical data , Female , Glomerular Filtration Rate , Humans , Kidney Failure, Chronic/diagnosis , Kidney Failure, Chronic/epidemiology , Kidney Failure, Chronic/etiology , Male , Middle Aged , Romania/epidemiologyABSTRACT
INTRODUCTION: The solitary kidney (SK) may present increased vulnerability to nephrotoxicity because of adaptive phenomena. AIMS: Assessing the vulnerability of the SK with urinary tract infections (UTI) to gentamicin by means of urinary biomarkers (N-acetyl-beta-D-glucosaminidase (NAG) and urinary alpha-1-microglobulin), as well as glomerular filtration rate (GFR). METHODS: We studied 14 patients with SK with UTI (group A) (mean age 58.07 ± 13.61 years, mean duration of SK 13.55 ± 12.33 years) who were administered gentamicin for 7 days. Group B consisted by 17 patients with SK without any other associated renal pathology (average age 51.17 ± 9.39 years, average existence period of a single kidney 33.23 ± 21.73 years). We also included a third group (group C) represented by nine healthy individuals, with two kidneys. RESULTS: Increased values of urinary NAG were found in group B as compared to group C and alpha-1 microglobulin in group A as compared to group B. During treatment with gentamicin, increased values of both NAG and alpha-1-microglobulin in group A were found on day 7 as compared to values before treatment (day 7 NAG=18.99 ± 14.07 U/g creat versus day 0, NAG=5.15 ± 6.54 U/g creat, p=0.004; day 7 alpha-1-microglobulin=20.88 ± 18.84 mg/g creat versus day 0, urinary alpha-1-microglobulin=4.96 ± 6.57 mg/g creat, p=0.003). No statistically significant alterations of GFR were noticed after 7 days of treatment. CONCLUSIONS: We found the nephrotoxic effects of gentamicin at tubular level, but not at glomerular level. The nephrotoxic potential of gentamicin in patients with a SK can be monitored by assessing urinary biomarkers during treatment of UTI.
Subject(s)
Acetylglucosaminidase/urine , Alpha-Globulins/urine , Anti-Bacterial Agents/adverse effects , Gentamicins/adverse effects , Kidney Diseases/chemically induced , Kidney Diseases/diagnosis , Urinary Tract Infections/drug therapy , Adult , Biomarkers/urine , Female , Glomerular Filtration Rate , Humans , Kidney/abnormalities , Kidney Diseases/urine , Kidney Tubules, Proximal/drug effects , Male , Middle Aged , NephrectomyABSTRACT
BACKGROUND AND AIMS: In order to assess the role played by tubular epithelial cells (TEC) and interstitial vascular endothelial cells (VEC) in interstitial fibrogenesis in human glomerulonephritis, we studied the expression of markers of activated fibroblasts (α-smooth muscle actin (αSMA) and vimentin (Vim)) and of the transforming growth factor ß (TGFß), at the level of these cells. METHODS: We studied retrospectively 41 renal biopsies from patients with primary and secondary glomerulonephritis [24 males, 17 females, mean age 45.5 ± 12.9 years]. Immunohistochemistry using monoclonal antibodies (SMA, Vim, TGFß) was assessed using a semiquantitative score, that was correlated with biological and histological data (quantified using a scoring system in order to assess active-inflammatory and chronic-sclerotic/fibrotic lesions). RESULTS: The presence of SMA and Vim as markers of myofibroblasts was found in TECs and VECs. TEC Vim expression correlated with interstitial Vim expression (r = 0.38; p = 0.008), interstitial infiltrate (r = 0.31; p = 0.027), interstitial fibrosis (R = 0.25; p = 0.042), GFR (r = -0.35; p = 0.016), SMA (r = -0.42; p = 0.015), TGFß (r = 0.25; p = 0.046), and hemoglobin (r = -0.55; p < 0.001). VEC Vim expression showed indirect correlations with interstitial infiltrate (r = -0.32; p = 0.023) and interstitial fibrosis (r = -0.34; p = 0.017). CONCLUSION: Our study reflects the complexity of the involvement of VEC and mainly of TEC in fibrosis. The expression of mesenchymal markers at the tubular cell level (especially Vim) correlates with histological interstitial changes, with the decrease of renal function and more strongly with anemia.
Subject(s)
Epithelial Cells , Glomerulonephritis/pathology , Kidney Tubules/pathology , Actins/biosynthesis , Adolescent , Adult , Aged , Biomarkers , Endothelial Cells/metabolism , Epithelial Cells/metabolism , Female , Glomerulonephritis/metabolism , Humans , Immunohistochemistry , Male , Middle Aged , Retrospective Studies , Transforming Growth Factor beta/biosynthesis , Vimentin/biosynthesis , Young AdultABSTRACT
Cerebrovascular disease accounts for major neurologic disabilities in patients with type 2 diabetes mellitus (DM). A potential association of mitochondrial DNA (mtDNA) and inflammation with cerebral vessel remodeling in patients with type 2 DM was evaluated. A cohort of 150 patients and 30 healthy controls were assessed concerning urinary albumin/creatinine ratio (UACR), synaptopodin, podocalyxin, kidney injury molecule-1 (KIM-1), N-acetyl-ß-(D)-glucosaminidase (NAG), interleukins IL-17A, IL-18, IL-10, tumor necrosis factor-alpha (TNFα), intercellular adhesion molecule-1 (ICAM-1). MtDNA-CN and nuclear DNA (nDNA) were quantified in peripheral blood and urine by qRT-PCR. Cytochrome b (CYTB) gene, subunit 2 of NADH dehydrogenase (ND2), and beta 2 microglobulin nuclear gene (B2M) were assessed by TaqMan assays. mtDNA-CN was defined as the ratio of the number of mtDNA/nDNA copies, through analysis of the CYTB/B2M and ND2/B2M ratio; cerebral Doppler ultrasound: intima-media thickness (IMT)-the common carotid arteries (CCAs), the pulsatility index (PI) and resistivity index (RI)- the internal carotid arteries (ICAs) and middle cerebral arteries (MCAs), the breath-holding index (BHI). The results showed direct correlations of CCAs-IMT, PI-ICAs, PI-MCAs, RI-ICAs, RI-MCAs with urinary mtDNA, IL-17A, IL-18, TNFα, ICAM-1, UACR, synaptopodin, podocalyxin, KIM-1, NAG, and indirect correlations with serum mtDNA, IL-10. BHI correlated directly with serum IL-10, and serum mtDNA, and negatively with serum IL-17A, serum ICAM-1, and NAG. In neurologically asymptomatic patients with type 2 DM cerebrovascular remodeling and impaired cerebrovascular reactivity may be associated with mtDNA variations and inflammation from the early stages of diabetic kidney disease.
Subject(s)
DNA, Mitochondrial , Diabetes Mellitus, Type 2 , Diabetic Nephropathies , Inflammation , Humans , DNA, Mitochondrial/genetics , Male , Female , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/genetics , Middle Aged , Inflammation/genetics , Diabetic Nephropathies/genetics , Diabetic Nephropathies/pathology , Aged , Vascular Remodeling/genetics , Case-Control StudiesABSTRACT
INTRODUCTION: The solitary kidney (SK) is currently debated in the literature, as living kidney donation is extensively used and the diagnosis of congenital SK is frequent. Tubulointerstitial lesions associated with adaptive phenomena may occur early within the SK. AIMS: Analysis of the significance of urinary biomarkers in the assessment of tubulointerstitial lesions of the SK. METHODS: A cross-sectional study of 37 patients with SK included 18 patients-acquired SK (mean age 56.44 ± 12.20 years, interval from nephrectomy 10.94 ± 9.37 years), 19 patients-congenital SK (mean age 41.52 ± 10.54 years). Urinary NAG, urinary alpha-1-microglobulin, albuminuria, eGFR (CKD-EPI equation) were measured. RESULTS: In acquired SK, NAG increased in 60.66%, urinary alpha 1-microglobulin in 16.66%, albuminuria in 55.55% of patients. Inverse correlation with eGFR presented NAG (R(2 )= 0.537, p = 0.022), urinary alpha 1-microglobulin (R(2 )= 0.702, p = 0.001), albuminuria (R(2 )= 0.655, p = 0.003). In congenital SK, NAG increased in 52.63%, urinary alpha 1-microglobulin in 5.26%, albuminuria in 47.36% of patients. In this group, urinary biomarkers correlated inversely with eGFR: NAG (R(2 )= 0.743, p < 0.001), urinary alpha 1-microglobulin (R(2 )= 0.701, p = 0.001), albuminuria (R(2 )= 0.821, p < 0.001). Significant correlations were found between the urinary biomarkers in both groups. CONCLUSIONS: Urinary biomarkers allow a non-invasive, sensitive, early assessment of the tubular lesions of the SK. Urinary biomarkers of PT injury parallel renal function decline, thus complementing the estimation of GFR. Monitoring of PT dysfunction is mandatory in patients with SK.
Subject(s)
Acetylglucosaminidase/urine , Alpha-Globulins/urine , Kidney Diseases/urine , Adult , Aged , Albuminuria/etiology , Biomarkers/urine , Cross-Sectional Studies , Female , Glomerular Filtration Rate , Humans , Male , Middle AgedABSTRACT
A case of strongyloidiasis in a patient with membranoproliferative glomerulonephritis is reported. In our patient, strongyloidiasis evolved latently and became overt after corticotherapy, and it turned to be a very severe outcome and life-threatening complications, hyperinfection syndrome and upper digestive tract hemorrhage. Besides its well-known complications, steroid therapy may provide real surprises. The association of this therapy with strongyloidiasis may turn an undiagnosed inactive, chronic form of the disease into an active form within the framework of a hyperinfection syndrome which might lead to death. In our case, the diagnosis of strongyloidiasis was established only after duodenal biopsy was performed for upper digestive tract hemorrhage, which revealed the parasite. It should be underlined that under corticotherapy, the patient evolved favorably with regard to glomerular disease, while strongyloidiasis worsened. The outcome was positive after the patient was treated with albendazole and ivermectin. The diagnosis of strongyloidiasis is sometimes difficult to establish due to the fact that eosinophilia may be absent, while commonly utilized stool examinations may be negative. By analyzing our case, it may be assumed that the immune mechanisms involved in strongyloidiasis do not activate the glomerular nephropathy. On the contrary, these mechanisms seem to have an immunosuppressive effect. The "hygienic hypothesis" also needs to be considered. While on corticotherapy, patients with glomerulonephritis need immunologic and parasitologic monitoring. This is important for other immunodepressing diseases and for immunosuppressive drugs. If the patient has originated in a mining area, as is the case with our patient, or in endemic areas, this monitoring becomes mandatory. The case reflects the complexity of the interrelation between the immune mechanisms in glomerulonephritis and those in parasitic diseases, strongyloidiasis in our case.
Subject(s)
Glomerulonephritis, Membranoproliferative/drug therapy , Glucocorticoids , Strongyloides stercoralis , Strongyloidiasis , Superinfection , Albendazole/administration & dosage , Animals , Antiparasitic Agents/administration & dosage , Biopsy , Duodenoscopy/methods , Female , Gastrointestinal Hemorrhage/etiology , Gastrointestinal Hemorrhage/therapy , Glucocorticoids/administration & dosage , Glucocorticoids/adverse effects , Host-Parasite Interactions/drug effects , Humans , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/adverse effects , Ivermectin/administration & dosage , Middle Aged , Monitoring, Immunologic , Strongyloides stercoralis/drug effects , Strongyloides stercoralis/isolation & purification , Strongyloidiasis/complications , Strongyloidiasis/drug therapy , Strongyloidiasis/etiology , Strongyloidiasis/immunology , Strongyloidiasis/physiopathology , Treatment OutcomeABSTRACT
Immune mechanisms play an important role in the pathogenesis of glomerulonephritis (GN), with autoimmunity being the main underlying pathogenetic process of both primary and secondary GN. We present three autoimmune diseases mediated by different autoimmune mechanisms: glomerulonephritis in vasculitis mediated by anti-neutrophil cytoplasmic antibodies (ANCAs), glomerulonephritis mediated by anti-glomerular basement membrane antibodies (anti-GBM antibodies), and immune complex-mediated glomerulonephritis. Some of these diseases represent a common clinical and histopathologic scenario, namely rapidly progressive crescentic glomerulonephritis. This is a severe illness requiring complex therapy, with the main role being played by therapy aimed at targeting immune mechanisms. In the absence of immune therapy, the crescents, the characteristic histopathologic lesions of this common presentation, progress toward fibrosis, which is accompanied by end-stage renal disease (ESRD). The fact that three diseases mediated by different immunopathologic mechanisms have a common clinical and histopathologic picture reveals the complexity of the relationship between immunopathologic mechanisms and their clinical expression. Whereas most glomerular diseases progress by a slow process of sclerosis and fibrosis, the glomerular diseases accompanied by glomerular crescent formation can progress, if untreated, in a couple of months into whole-nephron glomerulosclerosis and fibrosis. The outcome of different immune processes in a common clinical and histopathologic phenotype reveals the complexity of the relationship of the kidney with the immune system. The aim of this review is to present different immune processes that lead to a common clinical and histopathologic phenotype, such as rapidly progressive crescentic glomerulonephritis.
ABSTRACT
(1) Introduction and Aims: Little is known about the relationship between renal pathology and gallbladder pathology, although the two organs (the gallbladder and the right kidney) are in close proximity to one another. If a renal abscess disseminates, the gallbladder would be one of the secondary organs involved. As the bile provides a favorable environment for the development of pathogenic germs, it allows for the development of acute cholecystitis, even if calculi are absent, thus resulting in the development of acute acalculous cholecystitis. The aim of our study was to analyze the association between acute acalculous cholecystitis (AAC) and renal abscesses. (2) Methods: A department-wide retrospective cohort observational study including 67 patients with renal abscesses, with a mean age of 34.5+/-16.21 years and with five males and 62 females, was conducted. All of the patients were examined by an abdominal ultrasound. The lab tests included CBC with differential liver enzymes and serum bilirubin (in order to assess alterations in the liver function which can be associated with AAC) and serum creatinine (in order to assess the renal function). Blood culture and urine culture tests were also performed. (3) Results: Of the 67 patients with renal abscesses, eight (11.94%) were associated with acute cholecystitis: four cases (5.97%) of acalculous cholecystitis and four cases (5.97%) of calculous cholecystitis, two of which presented biliary sludge (acute micro-calculous cholecystitis). All four cases of acute acalculous cholecystitis presented with sepsis, and there was one case of septic shock at onset. We did not observe an impairment in renal function in the patients presenting with acute acalculous cholecystitis, and hepatic impairment was inconstant and moderate. All of the cases had a favorable outcome after a prompt initiation of intensive antibiotic therapy; both the renal abscess and the acute acalculous cholecystitis receded without further complications. (4) Conclusions: The association of acute acalculous cholecystitis with renal abscesses could be related to the possibility of germ dissemination from the infectious focus. In the case of a renal abscess, careful clinical, lab, and imaging exams of the gallbladder are recommended in order to ensure early therapeutic intervention in the event of an association with acute acalculous cholecystitis.
ABSTRACT
INTRODUCTION AND AIMS: N-Acetyl-ß-D-glucosaminidase (NAG), a marker of renal tubular dysfunction, is increased in patients with lupus nephritis. In addition to the toxic effects of proteinuria, patients with lupus nephritis may exhibit other factors that contribute to tubular dysfunction, such as pathogenic antitubular basement membrane antibodies. The aim of our study was to assess urinary NAG, proteinuria, and glomerular filtration rate (GFR) before treatment and after 7 and 30 days of oral prednisone therapy in patients with lupus nephritis. METHODS: Ten patients with lupus nephritis, all females, mean age: 29.4 ± 10.17 years, were enrolled into the study. All the patients received oral prednisone 1 mg/kg. Twenty healthy subjects served as controls. We measured urinary NAG before treatment and after 7 and 30 days of oral prednisone therapy. Proteinuria, GFR, blood pressure, and side effects of therapy were also followed up. Urinary NAG was measured using the colorimetrical method and expressed as units per gram of creatinine (U/gCr). Statistical analysis (Wilcoxon signed ranks test and Wilcoxon rank sum test) was performed using SPSS 17. RESULTS: In the 10 patients with lupus nephritis, urinary NAG before treatment was 16.9 ± 13.39 U/gCr (P = 0.005 compared with controls). NAG in controls was 1.73 ± 0.51 U/gCr. Proteinuria before treatment was 3.84 ± 1.93 g/24 h. The GFR before treatment was 50.48 ± 11.98 mL/min/1.73 m². After 7 days of prednisone, urinary NAG was 23.55 ± 25.25 U/gCr (P = 0.878 compared with baseline, and P = 0.02 compared with controls). Proteinuria was 2.94 ± 1.3 g/24 h (P = 0.005 compared with baseline), and the GFR was 58.11 ± 13.64 mL/min/1.73 m² (P = 0.005 compared with baseline). After 30 days of prednisone, urinary NAG was 11.77 ± 12.18 U/gCr (P = 0.203 compared with baseline, P = 0.022 compared with the value after 7 days of prednisone, and P = 0.01 compared with controls). Proteinuria was 1.73 ± 0.68 g/24 h (P = 0.005 compared with baseline, and P = 0.005 compared with the value after 7 days of prednisone), and the GFR was 67.49 ± 16.42 mL/min/1.73 m² (P = 0.005 compared with baseline and P = 0.009 compared with the value after 7 days of prednisone). Blood pressure measurements did not show any significant changes. No major side effects of steroid therapy were noticed. CONCLUSIONS: Urinary NAG showed a significant reduction between 7 and 30 days of therapy. The reduction in urinary NAG set in later than the decline in proteinuria and the improvement in GFR. Further studies incorporating a longer follow-up are needed to observe whether the reduction in NAG persists upon continuation of prednisone therapy.
Subject(s)
Acetylglucosaminidase/urine , Anti-Inflammatory Agents/administration & dosage , Glomerular Filtration Rate/drug effects , Kidney Tubules/physiopathology , Lupus Nephritis/drug therapy , Lupus Nephritis/urine , Prednisone/administration & dosage , Administration, Oral , Adolescent , Adult , Biomarkers/urine , Female , Humans , Kidney Tubules/metabolism , Kidney Tubules/pathology , Lupus Nephritis/physiopathology , Proteinuria/drug therapy , Proteinuria/physiopathology , Proteinuria/urine , Time FactorsABSTRACT
CD34 cells in the interstitial infiltrates in glomerulonephritis (GN) could be the turning point between regenerative processes and interstitial fibrosis. The aim of our study was to assess the presence of CD34+ cells in the interstitial infiltrates in GN. A cross-sectional study of 33 patients with glomerulonephritis, mean age: 43.3 ±11.31 years, 20 male and 13 female, was conducted. Conventional stains, as well as immunohistochemistry for the CD34 antigen were employed on kidney biopsies. Strength of immunohistochemical reaction was assessed semi-quantitatively. Regarding the percentage of cases with CD34+ cells in the interstitial infiltrates out of 33 patients: cells of interstitial infiltrates were 27.3% positive. The percentage of cases showing CD34+ cells at the level of interstitial infiltrates was: 44.4% in FSGS, 14.3% in membranoproliferative GN, 28.6% in membranous nephropathy, 20% in mesangial proliferative GN, 0% in minimal change disease, and 50% in crescentic GN. With the exception of minimal change disease, CD34+ cells were found in the interstitial infiltrates in all histopathological forms of GN. Some of these cells were spindle-shaped fibroblast-like cells. As inflammation in the tubulointerstitial compartment either resolves or proceeds to fibrosis, aims at reversing this process will benefit from analyses of the interstitial infiltrates harboring CD34+ cells.
Subject(s)
Fibroblasts/pathology , Glomerulonephritis/pathology , Adult , Antigens, CD34/analysis , Cross-Sectional Studies , Disease Progression , Female , Fibrosis , Humans , Immunohistochemistry , MaleABSTRACT
Background: Endoscopic retrograde cholangiopancreatography (ERCP) represents a major pivotal point in gastrointestinal endoscopy. Little is known about acute kidney injury (AKI) post-ERCP. This study analyses the incidence, risk factors, and prognosis of post-ERCP AKI. Methods: A total of 396 patients were prospectively studied. AKI was defined by an increase in serum creatinine (SCr) ≥ 0.3 mg/dL or by an increase in SCr ≥ 50% in the first 48 h post-ERCP. Logistic regression analysis was used to identify the predictors of AKI and in-hospital mortality. A two-tailed p value < 0.05 was considered significant. Results: One hundred and three patients (26%) developed post-ERCP AKI. Estimated glomerular filtration rate (adjusted odds ratio (aOR) = 0.95, 95% confidence interval (CI): 0.94−0.96, p < 0.001), nonrenal Charlson Comorbidity Index (Aor = 1.19, 95% CI: 1.05−1.35, p = 0.006), choledocholithiasis (aOR = 4.05, 95% CI: 1.98−8.29, p < 0.001), and bilirubin (aOR = 1.1, 95% CI: 1.05−1.15, p < 0.001) were associated with post-ERCP AKI. Post-ERCP AKI was associated with longer hospital stay (p < 0.001) and with increased in-hospital mortality (7.76% versus 0.36%, p < 0.001). Moderate-to-severe (stage 2 and 3) AKI was independently associated with in-hospital mortality (aOR = 6.43, 95% CI: 1.48−27.88, p < 0.013). Conclusions: Post-ERCP AKI represented an important complication associated with longer hospital stay. Moderate-to-severe post-ERCP AKI was an independent risk factor for in-hospital mortality.
ABSTRACT
INTRODUCTION: The aim of our study was to clarify the hypothesis that proximal tubule (PT) dysfunction may be responsible for early diabetic nephropathy (DN), independently of preceding glomerular endothelial dysfunction. The pattern of endothelial dysfunction and its potential variability was evaluated in two vascular beds, the kidney and the brain. METHODS: A total of 68 normoalbuminuric type 2 diabetes mellitus (DM) patients were enrolled in a cross-sectional study and the following parameters were assessed: urinary albumin:creatinine ratio (UACR), urinary α(1)-microglobulin, urinary ß(2)-microglobulin, plasma asymmetric dimethyl-arginine (ADMA), serum creatinine, glomerular filtration rate (GFR), C-reactive protein (CRP), fibrinogen, HbA(1c); pulsatility and resistance indices in the internal carotid artery and middle cerebral artery and intima-media thickness (IMT) in the common carotid artery; cerebrovascular reactivity was evaluated through the breath-holding test. RESULTS: Plasma ADMA was increased in 12 patients (17.5%), urinary α(1)-microglobulin in 19 patients (27.9%) and urinary ß(2)-microglobulin in 16 patients (23.5%). Cerebral hemodynamic indices correlated with plasma ADMA, CRP, fibrinogen, duration of DM, HbA(1c) and GFR. ADMA correlated with fibrinogen, CRP, HbA(1c), duration of DM and GFR. There were no correlations between ADMA and UACR, and urinary α(1)-/ß(2)-microglobulin. Also, no correlations were found between urinary α(1)-/ß(2)-microglobulin and UACR, HbA(1c), duration of DM and GFR. CONCLUSION: The increase in urinary α(1)-/ß(2)-microglobulin precedes the stage of albuminuria. It may be assumed that early DN is related to PT dysfunction. Endothelial dysfunction plays a pivotal role in the brain vasculature, while its involvement in the development of early DN is not conditional on the occurrence of albuminuria.
Subject(s)
Albuminuria/physiopathology , Diabetes Mellitus, Type 2/physiopathology , Diabetic Nephropathies/physiopathology , Endothelium, Vascular/physiopathology , Glomerular Filtration Rate/physiology , Kidney Tubules, Proximal/physiopathology , Aged , Albuminuria/diagnosis , Albuminuria/pathology , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/pathology , Cardiovascular Diseases/physiopathology , Cross-Sectional Studies , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/pathology , Diabetic Nephropathies/diagnosis , Diabetic Nephropathies/pathology , Endothelium, Vascular/pathology , Female , Humans , Kidney Tubules, Proximal/pathology , Male , Middle AgedABSTRACT
INTRODUCTION: HBV and HCV chronic hepatitis can be accompanied by secondary renal disease. In addition, these patients receive antiviral drugs with potential nephrotoxicity. It is known that interferon (IFN) therapy in HCV-infected kidney transplant recipients is followed by rejection of the transplant in 50% of the cases. Ribavirin is contraindicated in hemodialyzed patients and in patients with a GFR <50 ml/min/1.73 m(2). IFN therapy requires dosage reduction and close monitoring in patients with a GFR <50 ml/min/1.73 m(2) and in patients with end stage renal disease. The aim of our study was to assess the nephrotoxicity of antiviral drugs in patients with chronic hepatitis by measuring three renal biomarkers: urinary albumin, N-acetyl-ß-D-glucosaminidase (NAG) and α 1-microglobulin, as well as glomerular filtration rate (GFR-MDRD4) before and at 6 months of therapy. METHODS: Fifty-five patients (28 male and 27 female, with a mean age of 47.85 ± 12.03 years) with chronic hepatitis (40 patients with HCV, 13 patients with HBV, 1 patient with HBV+HCV, and 1 patient with HBV+HDV) were enrolled into the study. Different antiviral drug associations were used on a case-by-case basis. The 40 patients with HCV chronic hepatitis received either Peg-IFN-α 2a+Ribavirin (37 patients) or Peg-IFN-α 2b+Ribavirin (3 patients). The 13 patients with HBV chronic hepatitis received Peg-IFN-α 2a (9 patients), Lamivudine (2 patients), Entecavir (1 patient), or Adefovir (1 patient). The patient with HBV+HCV chronic hepatitis received Peg-IFN-α 2a+Ribavirin. The patient with HBV+HDV chronic hepatitis received IFN-α 2a. Urinary albumin (ELISA), NAG (colorimetrical method), α 1-microglobulin (ELISA), and serum creatinine were measured before and at 6 months of antiviral therapy. Urinary markers were expressed as either mg/gCr (for albumin and α 1-microglobulin) or U/gCr (for NAG). Statistical analysis (Pearson's correlation coefficient, paired t-test and χ(2)-test) was performed. RESULTS: At 6 months of therapy urinary albumin/gCr did not increase significantly: 16.58 ± 23.39 vs. 15.85 ± 24.96 mg/gCr before therapy, p = 0.87. Urinary NAG/gCr did not increase significantly: 4.21 ± 3.37 vs. 3.83 ± 3.2 U/gCr before therapy, p = 0.53. Urinary α 1-microglobulin/gCr was almost unchanged: 4.38 ± 4.47 vs. 4.38 ± 3.57 mg/gCr before therapy, p = 0.99. The GFR did not decline significantly: 92.41 ± 22.21 vs. 94.59 ± 36.1 ml/min/1.73 m(2) before therapy, p = 0.7. Ten patients (18.18%) were albuminuric before therapy, and 14 patients (25.45%) were albuminuric at 6 months of therapy, a non-significant increase (p = 0.35). We found a correlation between urinary albumin/gCr and NAG/gCr and between urinary albumin/gCr and α 1-microglobulin/gCr both at baseline and at 6 months of therapy: r = 0.54, p = 0.0005; r = 0.29, p = 0.03; r = 0.51, p = 0.0005; and r = 0.4, p = 0.002, respectively. In the patient receiving Adefovir, a known nephrotoxic drug, two of the three biomarkers (urinary albumin/gCr and NAG/gCr) increased, most notably NAG/gCr. Both HCV and HBV chronic hepatitis therapy were associated with non-significant changes in renal biomarker excretion and GFR. CONCLUSIONS: With the exception of Adefovir, all of the drug associations used in this study were safe.
Subject(s)
Adenine/analogs & derivatives , Albuminuria/chemically induced , Antiviral Agents/adverse effects , Hepatitis B, Chronic/drug therapy , Hepatitis C, Chronic/drug therapy , Interferon-alpha/adverse effects , Organophosphonates/adverse effects , Polyethylene Glycols/adverse effects , Ribavirin/adverse effects , Adenine/administration & dosage , Adenine/adverse effects , Adult , Albuminuria/blood , Albuminuria/urine , Antiviral Agents/administration & dosage , Drug Therapy, Combination/adverse effects , Drug Therapy, Combination/methods , Female , Hepatitis B, Chronic/blood , Hepatitis B, Chronic/urine , Hepatitis C, Chronic/blood , Hepatitis C, Chronic/urine , Humans , Interferon-alpha/administration & dosage , Male , Middle Aged , Organophosphonates/administration & dosage , Polyethylene Glycols/administration & dosage , Recombinant Proteins/administration & dosage , Recombinant Proteins/adverse effects , Ribavirin/administration & dosage , Time FactorsABSTRACT
Balkan endemic nephropathy (BEN) is a disease found in Romania and neighboring countries in the Balkan area. In Romania, BEN is most prevalent in Mehedinti County, located in the South of Romania near the Danube River. The etiology of the disease is as yet unknown. One of the current hypotheses concerning BEN etiology is an involvement of aristolochic acid (AA). BEN bears many similarities to aristolochic nephropathy, which is developed due to the use of Chinese herbs as therapeutic remedies in slimming diets. This paper analyzes the involvement of therapeutic remedies based on AA in the BEN found in Mehedinti County, where these herbs have been traditionally used. The presence of AA in the plasma of BEN patients as well as of other subjects, including healthy relatives of these patients and other persons from the BEN-affected area, has been analyzed. No AA was detected in the plasma of the studied subjects. This proves the absence, at the current time, of an AA contribution in the analyzed subjects. Therapeutic remedies based on AA have been used in the BEN-affected area. We were not able to reveal direct relationships between these remedies and either the development of BEN in dialyzed patients or the development of urinary-tract tumors in dialyzed patients with urothelial tumors. Therapeutic remedies based on Aristolochiaclematitis may play a stimulating role in BEN with regard to its development and the development of urinary-tract tumors. There may be a relationship between BEN and cumulative previous exposure to low doses of AA due to the consumption of contaminated foodstuffs, which could add to any contributions by therapeutic remedies.
Subject(s)
Aristolochia , Aristolochic Acids/adverse effects , Balkan Nephropathy/chemically induced , Balkan Nephropathy/epidemiology , Beverages/adverse effects , Plant Extracts/adverse effects , Aristolochic Acids/administration & dosage , Aristolochic Acids/isolation & purification , Balkan Nephropathy/blood , Data Collection/methods , Female , Humans , Plant Extracts/administration & dosage , Plant Extracts/isolation & purification , Plant Leaves , Romania/epidemiologyABSTRACT
INTRODUCTION: Because dysfunction of the B-cell compartment is thought to be important in the pathogenesis of systemic lupus erythematosus (SLE), there has been a recent focus on therapies that target humoral immunity via multiple mechanisms. The aim of this paper was to demonstrate the importance of immunomonitoring in two cases with class II lupus nephritis on steroids who presented with a flare-up of disease. After a thorough work-up for infectious triggers of disease activity, conversion to another histopathological class of lupus nephritis was suspected. Deterioration of the patients' clinical condition made kidney biopsy impossible, and as B-cell targeted therapy was considered, we decided to perform an immunophenotypic analysis and to tailor therapy to the results of the lymphocyte profile. As we incidentally found extremely low B-cell counts, any B-cell-targeted therapy was prohibited, and cyclophosphamide (Cy) was considered a viable therapeutic option. METHODS: We performed flow-cytometric lymphocyte (Ly) phenotyping (CD19, CD3, CD3CD4, CD3CD8, CD56/16) on two patients with class II lupus nephritis before and after two intravenous (i.v.) Cy pulse administrations. During all this time, patients were on steroids. RESULTS: Both patients showed extreme B-cell lymphopenia, a marker of active SLE, which was not greatly impacted by the treatment over the follow-up period. CONCLUSIONS: As current therapies are aimed at targeting the B cell, an important component of adaptive immunity, caution must be exercised before their use. In addition, monitoring of Ly subsets is essential due to the occurrence of extreme B-cell lymphopenia.
Subject(s)
B-Lymphocytes/pathology , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/drug therapy , Lymphopenia/etiology , Lymphopenia/pathology , Monitoring, Immunologic/methods , Adult , B-Lymphocytes/drug effects , Blood Pressure/drug effects , Creatinine/blood , Cyclophosphamide/pharmacology , Cyclophosphamide/therapeutic use , Fatal Outcome , Female , Humans , Immunophenotyping , Lupus Erythematosus, Systemic/blood , Lupus Erythematosus, Systemic/therapy , Lupus Nephritis/blood , Lupus Nephritis/complications , Lupus Nephritis/drug therapy , Lupus Nephritis/therapy , Lymphocyte Count , Lymphocyte Subsets/drug effects , Lymphocyte Subsets/pathology , Prednisone/therapeutic use , Proteinuria/etiology , Proteinuria/urine , Renal Dialysis , Treatment Outcome , Young AdultABSTRACT
Aim: An advanced proteomics platform for protein biomarker discovery in diabetic chronic kidney disease (DKD) was developed, validated and implemented. Materials & methods: Three Type 2 diabetes mellitus patients and three control subjects were enrolled. Urinary peptides were extracted, samples were analyzed on a hybrid LTQ-Orbitrap Velos Pro instrument. Raw data were searched using the SEQUEST algorithm and integrated into Proteome Discoverer platform. Results & discussion: Unique peptide sequences, resulted sequence coverage, scoring of peptide spectrum matches were reported to albuminuria and databases. Five proteins that can be associated with early DKD were found: apolipoprotein AI, neutrophil gelatinase-associated lipocalin, cytidine deaminase, S100-A8 and hemoglobin subunit delta. Conclusion: Urinary proteome analysis could be used to evaluate mechanisms of pathogenesis of DKD.
Subject(s)
Diabetes Mellitus, Type 2/physiopathology , Diabetic Nephropathies/diagnosis , Aged , Albuminuria/diagnosis , Albuminuria/urine , Biomarkers/urine , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/urine , Diabetic Nephropathies/urine , Female , Humans , Kidney Diseases/diagnosis , Kidney Diseases/urine , Kidney Function Tests , Male , Middle Aged , Peptides , Pilot Projects , Proteome/analysis , Proteomics/methodsABSTRACT
AIMS: To evaluate if there is a link between inflammation (expressed by inflammatory cytokines) and the early stage of diabetic kidney disease (DKD), as shown by markers of podocyte damage and proximal tubular (PT) dysfunction. METHODS: In this study were enrolled 117 type 2 DM patients (36-normoalbuminuria, 42-microalbuminuria, 39- macroalbuminuria), and 11 healthy subjects. Serum and urinary IL-1 alpha, IL-8, IL-18, urinary albumin:creatinine ratio (UACR), eGFR, biomarkers of podocyte damage (podocalyxin, synaptopodin, nephrin) and of PT dysfunction (KIM-1, NAG) were assessed. RESULTS: In multivariable regression urinary Il-1 alpha correlated positively with podocalyxin and NAG (pâ¯<â¯0.0001, R2=â¯0.57); urinary IL-8 correlated directly with synaptopodin, NAG, nephrin, and KIM-1 (pâ¯<â¯0.0001, R2â¯=â¯0.67); urinary IL-18 correlated directly with synaptopodin, NAG, and nephrin (pâ¯<â¯0.0001, R2â¯=â¯0.59). Serum IL-1 alpha correlated positively with nephrin, synaptopodin, NAG (Pâ¯<â¯0.0001, R2â¯=â¯0.68); serum IL-8 correlated directly with synaptopodin and NAG (pâ¯<â¯0.0001, R2â¯=â¯0.66); serum IL-18 correlated directly with NAG, KIM-1, and podocalyxin (pâ¯<â¯0.0001, R2=0.647). CONCLUSIONS: Pro-inflammatory interleukins are associated with podocyte injury and PT dysfunction in early DKD. These could exert a key role in the pathogenesis of early DKD, before the development of albuminuria.