Intradialytic periodized exercise improves cardiopulmonary fitness and respiratory function: A randomized controlled trial.

BACKGROUND: Chronic kidney disease (CKD) is a factor that predisposes to gradual physical deconditioning from its early stages leading to cardiorespiratory fitness and musculoskeletal system impairment. We evaluated the effects of combined and periodized intradialytic exercise training on cardiopulmonary fitness and respiratory function in HD subjects. METHODS: A randomized controlled trial with HD subjects was allocated into two groups: exercise group (EXG) and usual care group (UCG). EXG performed a 12-week combined and periodized intradialytic training. UCG maintained the HD routine. RESULTS: Thirty-nine HD subjects were analyzed (EXG = 20; UCG = 19). The EXG in comparison with the UCG showed improvements in peak oxygen consumption (Δ3.1[0.4-5.5] vs. -0.2[-2.0-1.5] ml/kg/min; p = 0.003), forced expiratory volume in the first second (Δ0.1[-0.0-0.1] vs. -0.0[-0.1-0.0] L; p = 0.022), forced vital capacity (Δ0.1[0.0-0.2] vs. -0.1[-0.2-0.0] L; p = 0.005), peak expiratory flow (Δ0.4[-0.7-1.2] vs. -0.1[-0.5-0.2] L; p = 0.046), and maximal inspiratory pressure (Δ7.35[-8.5-17.5] vs. -4.0[-18.0-12.0] cmH2 O; p = 0.028). The EXG, different from the UCG, did not worsen the maximal expiratory pressure (Δ0.1[-8.8-7.5] vs. -2.5[-15.0-9.0] cmH2 O; p = 0.036). Besides, EXG showed a significant improvement in quadriceps strength (32.05 ± 10.61 vs. 33.35 ± 11.62 kg; p = 0.042). CONCLUSIONS: The combined and periodized intradialytic exercise training improved cardiopulmonary fitness, respiratory function, inspiratory muscle strength, and quadriceps strength, beyond maintaining the expiratory muscle strength in HD subjects.

The spectrum of biopsy-proven glomerular diseases in a tertiary Hospital in Southern Brazil.

BACKGROUND: The prevalence and distribution of glomerular diseases differ among countries, and the indication to perform a kidney biopsy varies among centres. In this study, we assessed the prevalence of primary and secondary glomerulopathies based on histological diagnoses, and the correlation between glomerulopathies and demographic and clinical data was evaluated. METHODS: In this study, 1051 kidney biopsies were retrospectively reviewed between 2000 and 2018. Patient demographic, clinical and laboratory data were assessed. The prevalence of primary glomerulonephritis (PG) and secondary glomerulopathies (SG), as well as tubulointerstitial diseases (TIDs), hereditary nephropathies (HNs) and other diagnoses, were determined. The frequency of primary and secondary glomerulopathies was evaluated by age group, and the temporal variation in frequencies across three time periods (2000-2005, 2006-2011, and 2012-2018) was reported. RESULTS: The prevalence of SG predominated (52.4%), followed by PG (29.6%), other diagnoses (10.7%), TID (6.6%) and HN (1.1%). Among the primary forms of glomerular disease, focal segmental glomerulosclerosis (FSGS) was the most common (37.3%), followed by IgA nephropathy (IgAN, 24.4%), membranous nephropathy (MN, 18.6%) and minimal change disease (MCD, 8.4%). Lupus nephritis (LN, 41.1%) was most common in patients with SG, followed by diabetic kidney disease (DKD, 17.8%), systemic vasculitis (SV, 10.2%) and secondary FSGS (2nd FSGS, 10%). Nephrotic syndrome was the most common clinical presentation in patients with PG and also in patients with DRD and 2nd FSGS, whereas in patients with IgAN and SV, nephritic syndrome was the main presentation. For the age group between 18 and 50 years, LN, FSGS and IgAN predominated; for patients aged between 51 and 65 years, the proportion of DKD and 2nd FSGS increased, and SV was more common in patients > 65 years. The temporal variation in PG across the three time periods showed a statistically significant increase in IgAN (p = 0.001) and a reduction in FSGS over time (p < 0.001). In SG, there was a reduction in LN (p = 0.027) and an increase in DKD (p < 0.001) over time, with a tendency for 2nd FSGS to decrease over time (p = 0.053). CONCLUSIONS: In the studied kidney biopsy registry, FSGS and IgAN were the most prevalent diagnoses in patients with PG, and LN and DKD were the most prevalent in patients with SG. Nephrotic syndrome was the major indication for biopsy. When comparing the temporal variation in glomerulopathies, there was a reduction in FSGS and an increase in IgAN in patients with PGs over time, and for patients with SGs, there was a reduction in LN with an increase in cases of DKD over time.

Prevalence of the NPHS2 variants p.R229Q, p.A242V, and p.R138Q in patients with focal segmental glomerulosclerosis.

BACKGROUND: NPHS2 gene variants are associated with focal segmental glomerulosclerosis (FSGS) and steroid-resistant nephrotic syndrome (SRNS). In this study, the prevalence of NPHS2 variants p.R229Q, p.A242V, and p.R138Q was investigated in patients with familial or sporadic FSGS. MATERIALS AND METHODS: The sample consisted of 40 children and 70 adults diagnosed with FSGS confirmed by renal biopsy. Clinical and laboratory parameters were evaluated. Genotyping for the three single nucleotide polymorphisms (SNPs) was performed by real-time polymerase chain reaction: two variants in exon 5 (p.R229Q and p.A242V) and one in exon 3 (p.R138Q). Variants were correlated with ethnicity, clinical presentation, treatment response, and renal outcomes. RESULTS: Among the 40 children analyzed, 20% had familial and 80% sporadic FSGS and among adults, 4.3% had familial and 95.7% sporadic FSGS, respectively. Overall, SRNS was found in 70% of adults and 90% in children. Among children, variants were detected in 2 (5%) with sporadic FSGS, p.R229Q and p.A242V in 1 each. Among adults, variants were present in 9 (12.9%) patients, all with sporadic FSGS, p.R229Q in 4 and p.A242V in 5. No patient had the p.R138Q variant. Among adults, a trend of higher proteinuria at the end of follow-up (p = 0.06) was found in patients carrying a variant. There was no significant association between NPHS2 variants with the clinical presentation, dependence on immunosuppressive treatment, or renal outcomes. Regarding ethnicity, all patients carrying the p.R229Q variant were White, while 67% of carriers of the p.A242V variant were Black. CONCLUSION: In these patients with familial or sporadic FSGS, the prevalence of p.R229Q and p.A242V variants in children was 5% and in adults 12.9%. More studies of patients with FSGS could better define a strategy for genetic analysis and therapeutic management.

NLRP3 Inflammasome Modulation by Melatonin Supplementation in Chronic Pristane-Induced Lupus Nephritis.

Lupus nephritis (LN) is a kidney inflammatory disease caused by systemic lupus erythematosus (SLE). NLRP3 inflammasome activation is implicated in LN pathogenesis, suggesting its potential targets for LN treatment. Melatonin, an endogenous indoleamine, is considered an important multitasking molecule that has been reported to have anti-inflammatory effects by inhibiting nuclear factor-kappa B (NF-κB)-mediated inflammatory responses in vivo. This molecule has also protective effects against the activation of the inflammasomes and, in particular, the NLRP3 inflammasome. Thus, this work evaluated the effect of melatonin on morphological alteration and NLRP3 inflammasome activation in LN pristane mouse models. To evaluate the melatonin effects in these mice, we studied the renal cytoarchitecture by means of morphological analyses and immunohistochemical expression of specific markers related to oxidative stress, inflammation and inflammasome activation. Our results showed that melatonin attenuates pristane-induced LN through restoring of morphology and attenuation of oxidative stress and inflammation through a pathway that inhibited activation of NLRP3 inflammasome signaling. Our data clearly demonstrate that melatonin has protective activity on lupus nephritis in these mice that is highly associated with its effect on enhancing the Nrf2 antioxidant signaling pathway and decreasing renal NLRP3 inflammasome activation.

Kidney injury molecule-1 expression in human kidney transplants with interstitial fibrosis and tubular atrophy.

BACKGROUND: Kidney injury molecule-1 (KIM-1) is expressed in tubular epithelial cells after injury and may have a role in the development of renal graft fibrosis. In this study we evaluated the molecular and protein expressions of KIM-1 in dysfunctional allografts and also mRNA KIM-1 expression in urine as potential biomarkers of graft fibrosis. METHODS: Protein and mRNA levels in renal tissue and urinary sediment cells of 69 kidney transplant recipients that undertook for-cause graft biopsies were evaluated by immunohistochemistry and real-time polymerase chain reaction. The histopathology was classified according to the 2007 Banff schema. RESULTS: KIM-1 protein expression was increased in biopsies with interstitial fibrosis and tubular atrophy (IF/TA) compared with biopsies showing acute calcineurin inhibitor nephrotoxicity (CIN) (P <0.05). Kidney tissue KIM-1 mRNA signaling (in) was increased in biopsies with IF/TA compared with all other groups (P <0.05). In the urine cells KIM-1 mRNA was also increased in patients with IF/TA compared with patients with acute CIN (P <0.05). Significant correlations were found between KIM-1 protein and mRNA levels in tissue, between mRNA expressions in tissue and urine and between protein tissue expression and gene expression in the urine. CONCLUSIONS: KIM-1 seems to be a marker of kidney graft fibrosis. Urinary KIM-1 mRNA may become a useful non-invasive biomarker of the injuries that can trigger intra-graft fibrotic processes, such as interstitial fibrosis and tubular atrophy.

Performance of CKD-EPI equation to estimate glomerular filtration rate as compared to MDRD equation in South Brazilian individuals in each stage of renal function.

BACKGROUND: The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation seems to correct the overdiagnosis of chronic kidney disease (CKD) provided by Modification of Diet in Renal Disease (MDRD) equation. However, this point has not been tested in some ethnic groups. This study investigated the performance of MDRD and CKD-EPI equations in South Brazilian individuals. METHODS: This cross-sectional study included 354 individuals including healthy volunteers, diabetic and non-diabetic individuals with or without CKD. Glomerular filtration rate (GFR) was measured by the 51Cr-EDTA single-injection method (51Cr-GFR). Accuracy (P30), bias, and Bland-Altman agreement plots were evaluated. RESULTS: In the group as a whole, 51Cr-GFR was 87±37 (6-187), CKD-EPI eGFR, 82±30 (6-152), and MDRD eGFR, 77±28 (6-156) mL/min/1.73 m2 (p<0.001 for all comparisons). Analyzing the subset of individuals with 51Cr-GFR <60 mL/min/1.73 m2, P30 values were, respectively, 76% and 84% for MDRD and for CKD-EPI (p<0.001) while for 51Cr-GFR ≥60 mL/min/1.73 m2, P30 values were 57.5% for both equations (p=1.000). For MDRD and CKD-EPI, mean bias were negative for GFRs <60 (-11 vs. -12, p=0.221) and positive for values >60 (16 vs. 9, p<0.001). In multivariate analysis, absolute bias was unfavorably influenced by measured GFR >60 (for MDRD) and being diabetic or younger (for CKD-EPI). CONCLUSIONS: CKD-EPI reduces GFR underestimation in individuals with GFRs >60, but still presents a quite low accuracy at this GFR range. Moreover, it tends to overestimate GFR in subjects with GFRs <60 mL/min/1.73 m2. CKD stages 1 and 2, diabetes and young age had a negative influence on the performance of the equations.

Reference values for glomerular filtration rate in healthy Brazilian adults.

BACKGROUND: Glomerular filtration rate (GFR) is the best index of renal function, but age, gender and ethnicity can putatively affect its values. The aim of this study was to establish reference values for GFR in healthy Brazilian subjects while taking these factors into account. METHODS: In this cross-sectional study, GFR was measured by the 51Cr-EDTA single-injection method. GFR reference values were developed according to CLSI Guidelines for Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory (CLSI C28 protocol). RESULTS: The age range of the 285 healthy individuals was 19 to 70 years, 57% were females, and GFR was 106 ± 18 mL/min/1.73 m(2). There was no difference between male and female GFRs (108 ± 18 vs. 104 ± 18 mL/min/1.73 m(2) respectively, P = 0.134), and reference values were therefore developed from the pooled sample. GFR values were lower in subjects aged ≥45 years as compared with those younger than 45 years (98 ± 15 vs.112 ± 18 mL/min/1.73 m(2), P < 0.001). Based on mean ± 2 SD, GFR reference values were 76 to 148 mL/min/1.73 m(2) for subjects younger than 45 years and 68 to 128 mL/min/1.73 m(2) for individuals older than 45 years, irrespective of gender. CONCLUSION: The age-adjusted reference intervals reported may be reliably adopted to evaluate kidney function, since they are based on recommended standards.

Analysis of FOXP3 gene and protein expressions in renal allograft biopsies and their association with graft outcomes.

BACKGROUND: The transcription factor FOXP3 is increased in acute renal rejection, but its influence on graft outcomes is unclear. This study correlated FOXP3 with dendritic cells and graft outcomes. METHODS: We assessed 96 kidney transplants undergoing allograft biopsy for cause. FOXP3 mRNA was analyzed by real-time polymerase chain reaction (PCR) and FOXP3 protein and DCsCD83(+) by immunohistochemistry. Graft function and survival were assessed at 5 years post-transplantation, as well as by independent predictors of graft loss. RESULTS: Intragraft FOXP3 gene and protein expression were significantly correlated (r = 0.541, p < 0.001). Both FOXP3 mRNA and protein were increased in patients with acute rejection (AR). High expression of FOXP3 mRNA or protein in biopsies did not correlate with clinical variables, but there was a trend to higher positive variation in the glomerular filtration rate (GFR) from biopsy to last follow-up. Patients with FOXP3-mRNA(high) had more DCsCD83(+) in biopsy, but these cells did not associate with AR. Five-year graft survival was not influenced by either FOXP3 mRNA or protein expressions. CONCLUSIONS: FOXP3 mRNA and protein had a good correlation in archival renal graft tissue. Increased FOXP3 expression was found in AR and FOXP3 associated with high numbers of DCs. However, both FOXP3 mRNA and protein was not associated with better allograft outcomes.

Estimation of pulmonary artery systolic pressure in hemodialysis patients and its association with cardiorespiratory fitness and pulmonary function.

PURPOSE: To evaluate the estimated pulmonary arterial systolic pressure (PASP) through transthoracic echocardiography in hemodialysis (HD) patients and associate it with cardiorespiratory fitness and pulmonary function. METHODS: This study was a cross-sectional analysis of HD patients that performed evaluations of cardiac function, cardiorespiratory fitness, and pulmonary function, through transthoracic echocardiography, cardiopulmonary exercise test, spirometry, and manovacuometry, respectively. All patients underwent the evaluations on a non-dialysis day. RESULTS: Thirty-five HD patients were evaluated and separated according to the presence of probable pulmonary hypertension (PH) (estimated PASP ≥ 35 mmHg) or not (estimated PASP < 35 mmHg). Those HD patients with probable PH had the worst cardiorespiratory fitness, evaluated by the peak oxygen consumption (VO2peak) (17.11 ± 4.40 versus 12.90 ± 2.73 mL/kg/min; p = 0.011), and pulmonary function, evaluated by absolute and predicted of forced vital capacity (FVC) (85.52 ± 12.29 versus 71.38 ± 11.63%; p = 0.005) and absolute and predicted of forced expiratory volume in the first second (FEV1) (83.37 ± 14.98 versus 69.21 ± 13.48%; p = 0.017). The secondary analysis showed that estimated PASP was correlated with VO2peak (r = - 0.508; p = 0.002), FVC (r = - 0.450; p = 0.007), and FEV1 (r = - 0.361; p = 0.033). Moreover, the adjusted odds ratio by HD vintage, dry weight and gender showed that increments in VO2peak (OR 1.62; CI 95% 1.04-2.54; p = 0.034), FVC (OR 39.67; CI 95% 1.74-902.80; p = 0.021), and FEV1 (OR 39.54; CI 95% 1.89-826.99; p = 0.018) were associated with 1-fold and 39-fold higher chance, respectively, for not having PH. However, all these associations were lost when age was included in the analysis. CONCLUSIONS: The HD patients with probable PH had the worst cardiorespiratory fitness and pulmonary function. Exploratory analyses showed that greater cardiopulmonary fitness was associated with better cardiac function. Moreover, increments in cardiorespiratory fitness and pulmonary function may increase the chance of not having PH.

Endothelin-1 and endothelin a receptor immunoreactivity is increased in patients with diabetic nephropathy.

BACKGROUND: Endothelin-1 (ET-1) is associated with progression of renal disease, acting as a vasoconstrictor and growth factor for mesangial cells. ET-1 and endothelin A receptor (ET-RA) might have a role in the development of diabetic nephropathy (DN). The aims of this study were to determine ET-1 and ET-RA expressions in patients with DN and to correlate these expressions with renal function and proteinuria. MATERIALS AND METHODS: This is a cross-sectional study comprising 13 patients with type 2 diabetes mellitus and DN, 10 patients with proteinuric IgA nephropathy, and 13 samples of normal kidney from tumor nephrectomies. Demographic and selected data were collected from medical charts. The distribution and intensity of ET-1 and ET-RA immunostaining in renal biopsies were determined by immunohistochemistry and these correlated with the estimated glomerular filtration rate (eGFR) and proteinuria. RESULTS: Patients with DN and IgA nephropathy on biopsy had markedly increased staining for ET-1 in endothelial cells of glomerular and peritubular capillaries when compared with controls (p < 0.001). ET-RA staining was also more intense and more diffuse in DN and IgA nephropathy than in controls (p = 0.019) and was restricted to tubular epithelial cells. A positive correlation was observed between ET-1 expression and proteinuria (r = 0.634, p = 0.027), but both ET-1 and ET-RA expressions did not correlate with eGFR. CONCLUSION: In this preliminary report, the higher expressions of ET-1 and ET-RA found in both DN and IgA nephropathy suggest a potential role for the endothelin system in DN as well as in other nondiabetic glomerular diseases.

Precision medicine implementation challenges for APOL1 testing in chronic kidney disease in admixed populations.

Chronic Kidney Disease (CKD) is a public health problem that presents genetic and environmental risk factors. Two alleles in the Apolipoprotein L1 (APOL1) gene were associated with chronic kidney disease; these alleles are common in individuals of African ancestry but rare in European descendants. Genomic studies on Afro-Americans have indicated a higher prevalence and severity of chronic kidney disease in people of African ancestry when compared to other ethnic groups. However, estimates in low- and middle-income countries are still limited. Precision medicine approaches could improve clinical outcomes in carriers of risk alleles in the Apolipoprotein L1 gene through early diagnosis and specific therapies. Nevertheless, to enhance the definition of studies on these variants, it would be necessary to include individuals with different ancestry profiles in the sample, such as Latinos, African Americans, and Indigenous peoples. There is evidence that measuring genetic ancestry improves clinical care for admixed people. For chronic kidney disease, this knowledge could help establish public health strategies for monitoring patients and understanding the impact of the Apolipoprotein L1 genetic variants in admixed populations. Therefore, researchers need to develop resources, methodologies, and incentives for vulnerable and disadvantaged communities, to develop and implement precision medicine strategies and contribute to consolidating diversity in science and precision medicine in clinical practice.

Enoxaparin versus unfractioned heparin as anticoagulant for continuous venovenous hemodialysis: a randomized open-label trial.

AIM: In this study we aimed to compare the efficacy and safety of enoxaparin with unfractioned heparin (UFH) as anticoagulant for continuous venovenous hemodialysis (CVVHD). METHODS: An open-label randomized controlled trial was carried out in an intensive care unit (ICU) where 40 patients with acute renal failure (ARF) who needed continuous renal replacement therapy were randomized to receive UFH (n=21) or enoxaparin (n=19). Coagulation parameters were evaluated, and antithrombotic activity of UFH was measured by activated partial thromboplastin time (aPTT) and for enoxaparin by anti-factor Xa activity. Primary outcomes were thrombosis of the extracorporeal circuit and bleeding, classified as major or minor. RESULTS: Minor bleeding episodes were observed only in patients anticoagulated with enoxaparin (26 vs. 0%, p=0.018). Comparing patients with or without bleeding after 24 hours of therapy, the level of anticoagulation tended to be higher (anti-factor Xa: 1.62 vs. 1.13 IU/mL, p=0.09) and the platelet count to be lower [107+/-53 vs. 229+/-84 (x10(3)/microL), p=0.09] in patients who bled, but without statistical difference. Filter life span of enoxaparin and UFH groups was similar (43+/-15 vs. 52+/-18 hr, p=0.10), as well as the proportion of circuit clotting. CONCLUSION: Weight-unadjusted enoxaparin in patients with ARF in CVVHD was associated with an increased rate of bleeding, a finding that addresses the need to adjust drug dose and to monitor anti-factor Xa activity during dialysis. No benefit to prolong dialysis circuit survival was found with enoxaparin. In patients who do not present contraindication for systemic anticoagulation, UFH remains an effective and low-cost option.

Uric acid and kidney damage in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organs; lupus nephritis (LN) is one of the most severe complications of SLE. In the kidneys, an intense inflammatory reaction affects the glomeruli and tubular interstitium. Uric acid has been considered a key molecule in the pathogenesis of some conditions such as metabolic syndrome, hypertension, and kidney disease as it is produced by injured cells and promotes immune-inflammatory responses. In this regard, high serum uric acid concentrations may be involved in the activation of some inflammatory pathways, associated with kidney damage in SLE. Therefore, the purpose of this article was to review the main physiological mechanisms and clinical data on the association between serum uric acid and kidney damage in SLE. Scientific evidence indicates that hyperuricemia has the potential to be an adjuvant in the development and progression of kidney manifestations in SLE. Uric acid may promote the activation of inflammatory pathways and the formation and deposition of autoantibodies in kidneys, leading to a reduction of glomerular filtration rate. Other potential mechanisms of this association include the presence of polymorphisms in the urate transporters, metabolic syndrome, use of some medications, and other situations associated with a reduced renal excretion of uric acid.

Urinary soluble VCAM-1 is a useful biomarker of disease activity and treatment response in lupus nephritis.

INTRODUCTION: Vascular cell adhesion molecule-1 (VCAM-1) is involved in the progression of glomerular and tubulointerstitial injury in lupus nephritis (LN) and can be easily assessed in urine. The aim of this study was to assess urinary soluble VCAM-1 (uVCAM-1) as a biomarker of disease activity and treatment response in LN. METHODS: This prospective study enrolled 62 patients with class III, IV or V LN diagnosed within the last 3 years and divided them in two groups: with and without active nephritis at the inclusion, each group with 31 patients. At each visit, a urine sample was collected for uVCAM-1 evaluation and the nephritis status was assessed. RESULTS: Median uVCAM-1 level was elevated in patients with active compared to inactive LN (P < 0.001). The ROC curve of uVCAM-1 demonstrated an AUC of 0.84 and a cutoff of 47.2 ng/mgCr yielded a good sensitivity (74.2%) and specificity (74.2%) for the diagnosis of active LN. A significant correlation was found between uVCAM-1 level and renal activity scores and traditional biomarkers of LN. The level of uVCAM-1 dropped in patients with active LN who went into remission (P < 0.001), increased in patients who went into activity (P = 0.002) and did not change in patients who remained inactive (P = 0.797). The level of uVCAM-1 peaked during the flare of LN (P < 0.05). CONCLUSION: The uVCAM-1 is a reliable biomarker that reflects renal disease activity and is useful for monitoring individual patients with lupus nephritis over time.

Markers of renal fibrosis: How do they correlate with podocyte damage in glomerular diseases?

BACKGROUND: Renal fibrosis is the result of the interaction of cellular and molecular pathways, which is induced by sustained glomerular injury and involves the podocytes and multiple profibrotic factors. In this study, we investigated the correlation of the mRNA expression of podocyte proteins and profibrotic factors with renal fibrosis measured in renal biopsies of patients with primary and secondary glomerulopathies. METHODS: Eighty-four adult patients with primary or secondary glomerular diseases and 12 controls were included. Demographic and clinical data were collected. Seventy-two percent of the renal biopsies were done less than one year from clinical disease manifestation. The quantification of the podocyte-associated mRNAs of alpha-actinin-4, podocin, and podocalyxin, as well as of the profibrotic factors TGF-ß1, CTGF, and VEGF-A were quantified by real-time polymerase chain reaction. The percent positive area of renal fibrosis was measured by immunohistochemistry staining, using anti-CTGF and anti-HHF35 antibodies and unpolarized Sirius Red. Correlations between the expression of tissue mRNAs and the positive area of fibrosis for the measured markers were made by Spearman's rank correlation coefficient. RESULTS: In relation to control biopsies, podocyte-specific proteins were downregulated in podocytopathies, in proliferative nephritis, in diabetic kidney disease (DRD), and in IgA nephropathy (IgAN). Messenger RNA of TGF-ß1, CTGF, and VEGF-A was upregulated in patients with podocytopathies and in DRD but not in proliferative nephritis and IgAN. Tissue mRNA expression of TGF-ß1, CTGF, and VEGF-A were strongly correlated with renal fibrosis, as measured by HHF35; however, the correlation, albeit significant, was moderate for Sirius Red and weak for CTGF. The percent positive area of renal fibrosis measured by Sirius Red was similar between podocytopathies and DRD and significantly higher in podocytopathies compared to IgAN or proliferative nephritis. CONCLUSIONS: In patients with glomerular diseases, the mRNA of TGF-ß1, CTGF, and VEGF-A correlated positively with the extent of renal fibrosis, and the positive area of fibrosis was larger in the podocytopathies and in DRD as measured by Sirius Red. The pathways connecting podocyte damage and activation of profibrotic factors to kidney tissue fibrosis need to be better investigated.

Anticoagulant-related nephropathy: systematic review and meta-analysis.

BACKGROUND: The aim of this study was to report the prevalence and mortality associated with anticoagulant-related nephropathy (ARN) through a systematic review of the literature. METHODS: Electronic searches were conducted in the Medline and EMBASE databases, and manual searches were performed in the reference lists of the identified studies. The studies were selected by two independent researchers, first by evaluating the titles and abstracts and then by reading the complete texts of the identified studies. Case series, cross-sectional studies, cohort studies and case-control studies reporting the prevalence and factors associated with ARN were selected. The methodological quality was assessed using the Newcastle-Ottawa scale. Meta-analyses of the prevalence of ARN and 5-year mortality using the random effects model were performed when possible. Heterogeneity was assessed using the I 2 statistic. RESULTS: Five studies were included. Prevalence of ARN ranged from 19% to 63% among the four included cohort studies. Meta-analysis of these resulted in high heterogeneity [I 2 96%, summary effect 31%; 95% confidence interval (CI) 22-42%]. Subgroup meta-analysis yielded an ARN prevalence of 20% among studies that included patients with fewer comorbidities (I 2 12%; 95% CI 19-22%). In a direct comparison, meta-analysis of the 5-year mortality rate between anticoagulated patients who had experienced ARN and anticoagulated patients without ARN, patients with ARN were 91% more likely to die (risk ratio = 1.91; 95% CI 1.22-3; I 2 87%). Risk factors for ARN that were reported in the literature included initial excessive anticoagulation, chronic kidney disease, age, diabetes, hypertension, cardiovascular disease and heart failure. CONCLUSIONS: ARN studies are scarce and heterogeneous, and present significant methodological limitations. The high prevalence of ARN reported herein suggests that this entity is underdiagnosed in clinical practice. Mortality in patients with ARN seems to be high compared with patients without this condition in observational studies.

Oral supplementation of melatonin protects against lupus nephritis renal injury in a pristane-induced lupus mouse model.

AIMS: Since lupus nephritis (LN) etiopathogenesis is not fully understood, herein we investigated the morphological basis of LN in mice induced with pristane. MAIN METHODS: To evaluate the melatonin effects in these animals, we studied the renal cytoarchitecture by means of morphological analyses, immunofluorescence expression of specific markers related to fibrosis, oxidative stress, inflammation and apoptosis. KEY FINDINGS: We observed that pristane-LN mice have serious alterations in the kidney cytoarchitecture, i.e. tubular degeneration, glomerular hypercellularity, matrix mesangial expansion and interstitial inflammation. The pristane-induced LN mice treated with melatonin exhibited a well preserved cytoarchitecture. SIGNIFICANCE: Our results document that LN etiopathogenesis is related to both tubular damage and glomerular lesions. We suggest that it is essential to take in consideration both these lesions for LN diagnosis and classification. Clearly, we show that the use of melatonin may be a possible therapeutic strategy for improvement the renal injury in this disorder.

Protective effects of quercetin treatment in a pristane-induced mouse model of lupus nephritis.

INTRODUCTION: Lupus nephritis (LN) is one of the most severe complications of systemic lupus erythematosus. As murine models of LN are valuable tools to better understand its pathophysiology and to search for new effective treatments, we investigated the effects of the bioflavonoid quercetin on pristane-induced LN mice through histomorphological analyses. METHODS: Immunofluorescence and biochemical assays were used to evaluate the expression of markers of inflammation (interleukin-6, IL-6; tumour necrosis factor-α, TNF-α), oxidative stress (catalase, CAT; superoxide dismutase 1, SOD1; thiobarbituric acid reactive substances, TBARS), apoptosis (Bax), and fibrosis (transforming growth factor-ß1, TGF-ß1). Glomerular and tubular ultrastructure was analysed, and tissue messenger RNA of podocin, podoplanin and α3ß1-integrin were quantified using the real-time polymerase chain reaction. RESULTS: Pristane-induced LN mice showed severe kidney injury, characterized by increased proteinuria, glomerular mesangial expansion and inflammation, high expression of the pro-fibrotic, apoptotic and prooxidant markers and reduction of antioxidants. In the kidney ultrastructure, foot process (FP) effacement, apoptotic mesangial cells and abnormal mitochondria with disrupted cristae were observed, along with suppressed tissue mRNA of podocin, podoplanin and α3ß1-integrin. Treatment with quercetin in the pristane-induced LN mice model was nephroprotective, decreasing proteinuria levels and significantly lowering tissue expression of IL-6, TNF-α, TGF-ß1, Bax and TBARS. Simultaneously, quercetin significantly increased CAT and SOD1 expressions in these mice. In addition, it was observed improvement of the kidney ultrastructure, and tissue mRNA of podocin, but not podoplanin and α3ß1-integrin, was restored to the levels found in the control mice. CONCLUSION: In conclusion, these findings provide experimental evidence of the renoprotective effects of quercetin in the pristane-induced LN mice model. We suggest that quercetin effectively ameliorates the kidney damage caused by pristane, a bioflavonoid to be further evaluated as a new therapeutic strategy in this disease.

[Chronic renal disease, inflammation and atherosclerosis: new concepts about an old problem]. / Doença renal crônica, inflamação e aterosclerose: novos conceitos de um velho problema.

Chronic kidney disease (CKD) has reached epidemic proportions in the last few years, generating an emergent public health problem. Common risk factors for CKD and cardiovascular disease (CVD) are now well known resulting in a high prevalence rate of cardiovascular events which are the main cause of death in CKD patients. Development of accelerated atherosclerosis is related to traditional risk factors such as diabetes mellitus, arterial hypertension, dislipidemia and smoking, but recently other non traditional factors were found to be significantly associated with cardiovascular mortality, including inflammation, oxidative stress, endothelial dysfunction and uremia, even at early stages of CKD. Inflammatory markers such as C-reactive protein, interleukin 6 and fibrinogen are all correlated with cardiovascular death. The MIA syndrome is characterized by the association between inflammation, malnutrition and accelerated atherosclerosis, a condition commonly found in uremic patients, which is related to the genesis of CVD. Other important factors are the high level of oxidative stress, expressed by oxidized lipids, proteins and carbohydrates (AGES) (Advanced Glycation End Products), which cause tissue damage and endothelial dysfunction, that is aggravated by the uremic environment and other factors. These alterations are the basis for the pathogenic process of atherosclerosis and CVD in CKD patients, contributing to their high morbidity/mortality. This article is an updated review of the mechanisms of inflammation and oxidative stress and their relation to atherosclerosis in CKD.

Acute effects of intradialytic aerobic exercise on solute removal, blood gases and oxidative stress in patients with chronic kidney disease.

INTRODUCTION: Hemodialysis contributes to increased oxidative stress and induces transitory hypoxemia. Compartmentalization decreases the supply of solutes to the dialyzer during treatment. The aim of this study was to investigate the acute effects of intradialytic aerobic exercise on solute removal, blood gases and oxidative stress in patients with chronic kidney disease during a single hemodialysis session. METHODS: Thirty patients were randomized to perform aerobic exercise with cycle ergometer for lower limbs during 30 minutes with intensity between 60-70% of maximal heart rate, or control group (CG). Blood samples were collected prior to and immediately after exercise or the equivalent time in CG. Analysis of blood and dialysate biochemistry as well as blood gases were performed. Mass removal and solute clearance were calculated. Oxidative stress was determined by lipid peroxidation and by the total antioxidant capacity. RESULTS: Serum concentrations of solutes increased with exercise, but only phosphorus showed a significant elevation (p = 0.035). There were no significant changes in solute removal and in the acid-base balance. Both oxygen partial pressure and saturation increased with exercise (p = 0.035 and p = 0.024, respectivelly), which did not occur in the CG. The total antioxidant capacity decreased significantly (p = 0.027). CONCLUSION: The acute intradialytic aerobic exercise increased phosphorus serum concentration and decreased total antioxidant capacity, reversing hypoxemia resulting from hemodialysis. The intradialytic exercise did not change the blood acid-base balance and the removal of solutes.