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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 (VO 2peak ) (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 (FEV 1 ) (83.37 ± 14.98 versus 69.21 ± 13.48%; p = 0.017). The secondary analysis showed that estimated PASP was correlated with VO 2peak (r = - 0.508; p = 0.002), FVC (r = - 0.450; p = 0.007), and FEV 1 (r = - 0.361; p = 0.033). Moreover, the adjusted odds ratio by HD vintage, dry weight and gender showed that increments in VO 2peak (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 FEV 1 (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., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Giudicelli, De Souza, Veronese, Pereira, Hünemeier and Vianna.)

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] cmH 2 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] cmH 2 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., (© 2021 Wiley Periodicals LLC.)

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., (© 2021. The Author(s).)

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.

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.

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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.

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-β1, 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-β1, 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-β1, 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-β1, 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., Competing Interests: The authors have declared that no competing interests exist.

Renal involvement is one of the main complications of systemic lupus erythematosus, causing a significant impact on patients' morbidity and mortality. Renal biopsy is still the gold standard of diagnosis, but it has many limitations. In this sense, several recent studies aim to identify biomarkers that not only predict disease activity and renal histology, but also lead to earlier treatment. In previous studies, the soluble vascular cell adhesion molecule-1 measured in urine showed a strong association with the presence of lupus nephritis, with clinical and histological activity indexes of the disease and with more severe renal lesions. This paper reviews the main urinary biomarkers of lupus nephritis that have been studied, with special emphasis on vascular cell adhesion molecule-1 results.

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.

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-β1, TGF-β1). Glomerular and tubular ultrastructure was analysed, and tissue messenger RNA of podocin, podoplanin and α3β1-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 α3β1-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-β1, 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 α3β1-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.

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Patients on chronic hemodialysis tend to lose lean body mass and have sedentary behavior., Objective: To compare the level of physical activity and the morphology of the muscles pectoralis major and rectus abdominis of patients on hemodialysis with healthy subjects., Methods: We studied 17 patients and 17 healthy individuals. Muscle thickness were evaluated by ultrasound, and the level of physical activity by the International Physical Activity Questionnaire (IPAQ), long version., Results: The patients had lower thicknesses of the pectoralis major (5.92 ± 0.35 mm vs. 8.35 ± 0.62 mm, p < 0.001) and rectus abdominis (0.96 ± 0.10 mm vs. 2 21 ± 0.40 mm, p < 0.001) compared to healthy subjects. Patients were physically less active than healthy individuals: 1502.55(788.19-2513.00) MET-minutes/week vs. 2268.0(1680.0-4490,8) MET-minutes/week (p = 0.006); the weekly caloric expenditure of patients was also lower: 1384.0(480,7-2253.7) kcal/kg/week vs. 1680.0(1677.4-4950.0) kcal/kg/week (p = 0.010). The average time spent sitting per week of the patients was higher than in healthy subjects (394.0 ± 33.1 min/day vs. 293.0 ± 38.6, p = 0.009) as well as the average time spent sitting during weekend (460.0 ± 40.1 vs. 201.0 ± 10.7, p = 0.003)., Conclusion: Chronic renal failure patients on hemodialysis have sedentary behavior and lower muscle thickness of the trunk.

Introduction: Steroid-resistant focal segmental glomerulosclerosis (SR-FSGS) is a common glomerulopathy associated with nephrotic range proteinuria. Treatment goals are reduction in proteinuria, which can delay end-stage renal disease., Methods: Patients with SR-FSGS were enrolled in a randomized, double-blind placebo-controlled trial of fresolimumab, a monoclonal anti-transforming growth factor-β antibody, at 1 mg/kg or 4 mg/kg for 112 days, followed double-blind for 252 days (NCT01665391). The primary efficacy endpoint was the percentage of patients achieving partial (50% reduction) or complete (< 300 mg/g Cr) remission of proteinuria., Results: Of 36 enrolled patients, 10, 14, and 12 patients received placebo, fresolimumab 1 mg/kg, and fresolimumab 4 mg/kg, respectively. The baseline estimated glomerular filtration rate (eGFR) and urinary protein/creatinine ratio were 63 ml/min/1.73 m 2 and 6190 mg/g, respectively. The study was closed before reaching its target of 88 randomized patients. None of the prespecified efficacy endpoints for proteinuria reduction were achieved; however, at day 112, the mean percent change in urinary protein/creatinine ratio (a secondary efficacy endpoint) was -18.5% ( P  = 0.008), +10.5% ( P  = 0.52), and +9.0% ( P  = 0.91) in patients treated with fresolimumab 1 mg/kg, fresolimumab 4 mg/kg, and placebo, respectively. There was a nonsignificant trend toward greater estimated glomerular filtration rate decline in the placebo group compared to either of the fresolimumab-treated arms up to day 252., Discussion: The study was underpowered and did not meet the primary or secondary endpoints. However, fresolimumab was well tolerated and is appropriate for continued evaluation in larger studies with adequate power.

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.

Objectives: Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease with renal involvement in over half of the cases. In lupus nephritis (LN), podocytes are injured at the structural and molecular level. Spontaneous or induced animal models of SLE can reproduce the glomerular damage, similar to what is observed in humans. In this review, murine models focusing the podocyte injury were summarized, and therapeutic strategies to protect the podocyte cell were explored., Methods: Using the PubMed and MEDLINE databases from 1950 to 2015, literature search was conducted by article title and abstract, combining the following key words: "systemic lupus erythematosus," "lupus nephritis," "animal model," "podocyte injury," and "treatment.", Results: Published or in-press eligible studies that were published as full-length articles in English-language journals were considered. Articles were summarized according to podocyte structure and function, the podocyte injury resulting from spontaneous (NZB/W F1 hybrid, MRL/lpr, and BXSB-Yaa mice) or induced (chronic graft-versus-host disease and pristane) mice models of LN, and the protective effects of drug treatments on podocyte cell structure and function reported in these models., Conclusions: Murine models of SLE have proven useful for better comprehension of the multiple mechanisms involved in systemic autoimmunity that leads to LN. These critical tools should be considered when target therapies are designed to control this disorder., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Urinary biomarkers can predict the progression of chronic kidney disease (CKD). In this study, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and N-acetyl-β-D-glucosaminidase (NAG) were correlated with the stages of CKD, and the association of these biomarkers with CKD progression and adverse outcomes was determined. A total of 250 patients, including 111 on hemodialysis, were studied. Urinary KIM-1, NGAL, and NAG were measured at baseline. Patients not on dialysis at baseline who progressed to a worse CKD stage were compared with those who did not progress. The association of each biomarker and selected covariates with progression to more advanced stages of CKD, end-stage kidney disease, or death was evaluated by Poisson regression. NGAL was moderately correlated (rs=0.467, P<0.001) with the five stages of CKD; KIM-1 and NAG were also correlated, but weakly. Sixty-four patients (46%) progressed to a more advanced stage of CKD. Compared to non-progressors, those patients exhibited a trend to higher levels of KIM-1 (P=0.064) and NGAL (P=0.065). In patients not on dialysis at baseline, NGAL was independently associated with progression of CKD, ESKD, or death (RR=1.022 for 300 ng/mL intervals; CI=1.007-1.037, P=0.004). In patients on dialysis, for each 300-ng/mL increase in urinary NGAL, there was a 1.3% increase in the risk of death (P=0.039). In conclusion, urinary NGAL was associated with adverse renal outcomes and increased risk of death in this cohort. If baseline urinary KIM-1 and NGAL predict progression to worse stages of CKD is something yet to be explored.

The IgG4-related disease has a wide clinical spectrum where multiple organs can be affected, and the diagnosis depends on typical histopathological findings and an elevated IgG4 expression in plasma cells in the affected tissue. We describe the clinical presentation and evolution of a patient with acute tubulointerstitial nephritis, severe kidney failure and systemic manifestations such as lymphadenomegaly and chronic pancreatitis. The diagnosis was confirmed by the clinical picture and kidney and lymph node histopathology, in which immunohistochemistry of the lymphoid tissue showed policlonality and increased expression of IgG4, with a IgG4/total IgG ratio > 80%. The patient was treated with prednisone at a dose of 60 mg/day, followed by mycophenolate mofetil, and showed clinical and renal function improvement at 6 months of follow-up. The high index of suspicion of IgG4-related disease with multisystem involvement and the early treatment of this condition are essential to improve the prognosis of affected patients. Resumo A doença relacionada à IgG4 tem um espectro clínico amplo em que múltiplos órgãos podem ser afetados, e o diagnóstico depende de achados histopatológicos típicos e elevada expressão de IgG4 em plasmócitos no tecido afetado. Descrevemos o quadro clínico e a evolução de um paciente com nefrite túbulo-intersticial aguda, insuficiência renal grave e manifestações sistêmicas como linfoadenomegalias e pancreatite crônica. O diagnóstico foi confirmado pelas características clínicas e pela histopatologia renal e de linfonodo, na qual a imunohistoquímica mostrou tecido linfoide com policlonalidade e expressão aumentada de IgG4, com uma relação IgG4/IgG total > 80%. O paciente foi tratado com prednisona na dose de 60 mg/dia, seguido de micofenolato mofetil, e apresentou melhora clínica e da função renal depois de 6 meses de tratamento. O alto índice de suspeição da doença relacionada ao IgG4 com comprometimento multissistêmico e o tratamento precoce desta condição são primordiais para a melhora do prognóstico destes pacientes.

Introduction: Vitamin D reduces albuminuria in patients with chronic kidney disease (CKD) but its effects on glomerular podocytes are not entirely understood., Objective: To evaluate if cholecalciferol supplementation reduces the levels of podocyte-associated urine mRNAs in patients with CKD., Methods: A total of 27 patients with stages 2 to 4 CKD and suboptimal serum vitamin D [25(OH)D] levels were treated with cholecalciferol for 6 months. Serum 25(OH)D level, estimated glomerular filtration rate (eGFR), proteinuria, and urine mRNA of nephrin, podocin, podocalyxin, transient receptor potential cation channel 6, vascular endothelial growth factor A, and transforming growth factor beta were assessed before and after intervention., Results: eGFR declined at an average rate of -4.71 mL/min/1.73 m2 (p = 0.010 vs. baseline), being 28 ± 16 mL/min/1.73 m2 at six months. No changes in proteinuria or mineral and bone metabolism parameters were observed after cholecalciferol supplementation. Urinary podocyte-associated mRNAs did not change significantly after treatment. However, patients who achieved 25(OH)D level > 20 ng/mL at six months showed a trend of reduction of urinary nephrin and podocin mRNA levels; in patients with 25(OH)D that remained < 20 ng/mL there was a significant increase in urinary podocalyxin, and a trend of higher expression of urinary nephrin and podocin mRNA., Conclusion: Six months of cholecalciferol supplementation had no effect on urine podocyte-associated mRNA profile of patients with advanced CKD. The protective effect of vitamin D or its analogues on the glomerular podocyte should be investigated in early stages of CKD with a longer treatment period.

HIV infection has a broad spectrum of renal manifestations. This study examined the clinical and histological manifestations of HIV-associated renal disease, and predictors of renal outcomes. Sixty-one (64% male, mean age 45 years) HIV patients were retrospectively evaluated. Clinical presentation and renal histopathology were assessed, as well as CD4 T-cell count and viral load. The predictive value of histological lesion, baseline CD4 cell count and viral load for end-stage renal disease (ESRD) or death were determined using the Cox regression model. The outcomes of chronic kidney disease (CKD) and ESRD or death were evaluated by baseline CD4 cell count. The percent distribution at initial clinical presentation was non-nephrotic proteinuria (54%), acute kidney injury (28%), nephrotic syndrome (23%), and chronic kidney disease (22%). Focal segmental glomerulosclerosis (28%), mainly the collapsing form (HIVAN), acute interstitial nephritis (AIN) (26%), and immune complex-mediated glomerulonephritis (ICGN) (25%) were the predominant renal histology. Baseline CD4 cell count ≥ 200 cells/mm3 was a protective factor against CKD (hazard ratio=0.997; 95%CI=0.994-0.999; P=0.012). At last follow-up, 64% of patients with baseline CD4 ≥ 200 cells/mm3 had eGFR >60 mL·min-1·(1.73 m2)-1 compared to the other 35% of patients who presented with CD4 <200 cells/mm3 (log rank=9.043, P=0.003). In conclusion, the main histological lesion of HIV-associated renal disease was HIVAN, followed by AIN and ICGN. These findings reinforce the need to biopsy HIV patients with kidney impairment and/or proteinuria. Baseline CD4 cell count ≥ 200 cells/mm3 was associated with better renal function after 2 years of follow-up.

Levamisole has been increasingly used as an adulterant of cocaine in recent years, emerging as a public health challenge worldwide. Levamisole-associated toxicity manifests clinically as a systemic vasculitis, consisting of cutaneous, hematological, and renal lesions, among others. Purpura retiform, cutaneous necrosis, intravascular thrombosis, neutropenia, and less commonly crescentic nephritis have been described in association with anti-neutrophil cytoplasmic antibodies (ANCAs) and other autoantibodies. Here we report the case of a 49-year-old male who was a chronic cocaine user, and who presented spontaneous weight loss, arthralgia, and 3 weeks before admission purpuric skin lesions in the earlobes and in the anterior thighs. His laboratory tests on admission showed serum creatinine of 4.56 mg/dL, white blood count 3,800/μL, hemoglobin 7.3 g/dL, urinalysis with 51 white blood cells/μL and 960 red blood cells/μL, and urine protein-to-creatinine ratio 1.20. Serum ANCA testing was positive (>1:320), as well as serum anti-myeloperoxidase and anti-proteinase 3 antibodies. Urine toxicology screen was positive for cocaine and levamisole, with 62.8% of cocaine, 32.2% of levamisole, and 5% of an unidentified substance. Skin and renal biopsies were diagnostic for leukocytoclastic vasculitis and pauci-immune crescentic glomerulonephritis, respectively. The patient showed a good clinical response to cocaine abstinence, and use of corticosteroids and intravenous cyclophosphamide. Last serum creatinine was 1.97 mg/dL, white blood cell count 7,420/μL, and hemoglobin level 10.8 g/dL. In levamisole-induced systemic vasculitis, the early institution of cocaine abstinence, concomitant with the use of immunosuppressive drugs in severe cases, may prevent permanent end organ damage and associate with better clinical outcomes.

Objective: The aim of this study was to correlate different degrees of excess weight with the expression of podocyte-associated messenger RNAs (mRNAs) in urine., Methods: The sample comprised 83 patients with overweight or obesity class I, II, or III and 18 healthy controls. The expression of nephrin, podocin, podocalyxin, α-actinin-4, α3β1integrin, vascular endothelial growth factor, and transforming growth factor-beta (TGF-β1 ) mRNA in urine was quantified with the real-time polymerase chain reaction. mRNA expression was correlated with body mass index, the metabolic syndrome, albuminuria, and inflammation., Results: Adults with obesity class III had higher levels of serum lipids, glucose, HbA1C, insulin resistance, and C-reactive protein (P < 0.05), with 85% of the subjects meeting criteria for the metabolic syndrome (P < 0.001 vs. other groups). Urinary podocyte-associated mRNAs were higher in adults with obesity class III than in other groups (P < 0.05). Patients with overweight or obesity class I or II also had higher levels of podocyte mRNAs than controls: nephrin (P = 0.021), α-actinin-4 (P = 0.014), α3β1integrin (P = 0.036), and TGF-β1 (P = 0.005). Metabolic syndrome, hyperinsulinemia, and C-reactive protein were correlated with podocyturia, but only higher insulin levels were related regardless of obesity., Conclusions: Severe obesity and hyperinsulinemia were associated with higher urinary expression of podocyte-associated mRNAs, even at normal urinary albumin excretion rates., (© 2015 The Obesity Society.)

Aim: Glomerular deposition of immune complexes and inflammation induce podocyte injury in lupus nephritis (LN). This study hypothesized that the severity of the histological lesions of LN affects podocyte-associated mRNAs profiles in kidney tissue and in urine., Methods: Thirty-three patients with LN were grouped according to the presence of mild mesangial (classes I and II) or moderate-to-severe immune complex deposition, proliferation and/or inflammation (classes III, IV and V) in kidney biopsy. Tissue and urine mRNA of nephrin, podocin, podocalyxin, α-actinin-4, transient receptor potential cation channel 6, and of growth factors VEGF-A and TGF-β1 and the transcription factor FOXP3 were measured using real time polymerase chain reaction. These mRNAs were correlated with histological severity of LN, extent of glomerular immune deposits, and tissue infiltrating cells., Results: Podocyte-associated mRNAs were inhibited in renal tissue of patients with LN irrespective of histological class when compared to controls. However, significantly higher expression of podocyte mRNAs in urine, including those of growth factors and FOXP3, were found in patients with moderate-to-severe nephritis, mostly in class III and IV proliferative forms. The number of invading CD8+ T cells, B cells and macrophages correlated positively with urine podocyte-associated mRNAs. Urine podocyte mRNAs also correlated with proteinuria., Conclusions: Inhibition of podocyte-associated mRNAs in kidney tissue suggests that podocyte injury occurs regardless of class severity of LN. Increased urinary excretion of podocyte mRNAs, mostly in patients with moderate-to-severe lesions, may reflect a greater burden of glomerular damage with detachment of podocytes into the urine.

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.

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.

Objectives: To evaluate B-cell expression patterns and association with function and survival in dysfunctional kidney allografts., Materials and Methods: There were 110 kidney transplant recipients included who had for-cause biopsies. Demographic and transplant data were collected. Immunostaining for B cells, plasma cells, and C4d was performed by the immunoperoxidase technique in paraffin-embedded samples. Circulating antihuman leukocyte antigen donor-specific antibodies were detected in a single-antigen assay at biopsy. The main outcomes were kidney graft survival and function. The patients were evaluated in 3 groups according to the Banff classification: no rejection (40 patients), T-cell-mediated rejection (50 patients), and antibody-mediated rejection (20 patients)., Results: The CD138-positive plasma cell-rich infiltrates predominated in antibody-mediated rejection and were associated with stronger reactivity against panel antibodies (r = 0.41; P ≤ .001) and positive donor-specific antibodies (r = 0.32; P ≤ .006). The CD20-positive lymphocytes were associated with T-cell-mediated rejection, increased human leukocyte antigen mismatch, and frequency of retransplant. The CD138-positive cell infiltrates also were significantly greater in patients who had late than early rejection. There was no correlation between cellular CD20 and CD138 expression, and neither CD20 nor CD138 predicted worse graft function or survival. Other markers of antibody-mediated rejection such as C4d and donor-specific antibodies were associated with worse graft function and survival at 4 years after transplant. In multivariate analysis, C4d was the only risk factor associated with graft loss., Conclusions: After kidney transplant, CD20-positive B-cell infiltrates were associated with T-cell-mediated rejection, and CD138-positive plasma cells were associated with antibody-mediated rejection. Graft loss was associated with the presence of C4d.

Aim: It is not clear how the podocyte damage manifests in different glomerulopathies. This study evaluated the podocyte-associated mRNA profiles in renal tissue and urine of patients with proliferative (PGs) or non-proliferative (NPGs) glomerulopathies., Methods: Messenger RNA levels of nephrin, podocin, podocalyxin, synaptopodin, and alpha-actinin-4 were measured in the kidney tissue and urinary cells by real-time polymerase chain reaction. Podocyte-associated mRNAs were correlated with proteinuria and renal function, and the effect of immunosuppressive treatment of PGs and NPGs on urine mRNAs was assessed up to one year of follow up., Results: Podocyte-associated mRNAs were expressed consistently less in kidney tissue from patients with NPGs, and urinary podocyte mRNA levels were significantly higher in the PG group. After six months of immunosuppressive therapy, patients with PGs showed a significant reduction in the expression of podocin, podocalyxin, and alpha-actinin-4 compared with baseline (p<0.001). In the NPG group, alpha-actinin-4 levels decreased (p=0.008), and there was also a trend toward reduced podocalyxin mRNA (p=0.08). Urine podocyte-associated mRNAs correlated with the level of proteinuria at baseline and at six months, and there was a trend toward an inverse correlation between urinary mRNAs and kidney function at one year of follow up., Conclusions: Podocyte-associated mRNAs were inhibited in kidney tissue concomitantly with their increase in urine in these patients with glomerulopathies. Different profiles of mRNA expression were seen, pointing to a higher degree of intra-renal podocytopenia in the NPGs and of podocyturia in the PGs. The immunosuppressive therapy effectively reduced the urinary levels of podocyte-associated mRNAs.

Aim: The accuracy of equations that estimate the glomerular filtration rate (GFR) in renal transplant patients has not been established; thus their performance was assessed in stable renal transplant patients., Methods: Renal transplant patients (N.=213) with stable graft function were enrolled. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used as the reference method and compared with the Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), Mayo Clinic (MC) and Nankivell equations. Bias, accuracy and concordance rates were determined for all equation relative to CKD-EPI., Results: Mean estimated GFR values of the equations differed significantly from the CKD-EPI values, though the correlations with the reference method were significant. Values of MDRD differed from the CG, MC and Nankivell estimations. The best agreement to classify the chronic kidney disease (CKD) stages was for the MDRD (Kappa=0.649, P<0.001), and for the other equations the agreement was moderate. The MDRD had less bias and narrower agreement limits but underestimated the GFR at levels above 60 mL/min/1.73 m2. Conversely, the CG, MC and Nankivell equations overestimated the GFR, and the Nankivell equation had the worst performance. The MDRD equation P15 and P30 values were higher than those of the other equations (P<0.001)., Conclusion: Despite their correlations, equations estimated the GFR and CKD stage differently. The MDRD equation was the most accurate, but the sub-optimal performance of all the equations precludes their accurate use in clinical practice.

The aim of this study was to report the clinical findings and the screening of mutations of amelogenin gene of a 7-year-old boy with amelogenesis imperfecta (AI). The genomic DNA was extracted from saliva of patient and his family, followed by PCR and direct DNA sequencing. The c.261C>T mutation was found in samples of mother, father, and brother, but the mutation was not found in the sequence of the patient. This mutation is a silent mutation and a single-nucleotide polymorphism (rs2106416). Thus, it is suggested that the mutation found was not related to the clinical presence of AI. Further research is necessary to examine larger number of patients and genes related to AI.

This study aimed at evaluating how well dentists understand medical emergency/urgency procedures and issues during dental treatment at a hospital specialized in cleft lip and palate. It comprised a hundred dentists from the Hospital for Rehabilitation of Craniofacial Anomalies, University of São Paulo (HRAC/USP), Brazil, from different dental specialties. A questionnaire was applied to evaluate their knowledge of medical emergencies/urgencies from June through September 2011. The questionnaire was anonymous, confidential and constructed with closed questions and either yes-no or multiple-choice responses. Results showed that most professionals (87%) were trained in basic life support (BLS), but only 43% considered themselves capable of providing first aid and performing the necessary maneuvers. Most participants (94%) claimed that they knew the difference between medical urgencies and emergencies, and 69% had BLS training in their undergraduate courses, as opposed to 37%, during their specialization. Some participants (23%) mentioned that they had received knowledge of the subject during extracurricular courses and/or graduate courses (12%). Only 9% had not been educated on the subject; however, all participants showed interest in attending a course in BLS. In regard to assessing training that dentists who attended BLS courses received, 49% were satisfied and 42% were dissatisfied. Results of the present study emphasize that dentists from HRAC/USP have little knowledge about BLS procedures to perform them. Dentists must gain adequate education and training to minimize possible technical, ethical and legal problems associated with dental practice. It is necessary to improve both knowledge and practice in order to become well-qualified practitioners.

The aim of this study was to investigate the occurrence of mutations in the amelogenin gene (AMELX) in patients with cleft lip and palate (CLP) and enamel defects (ED). A total of 165 patients were divided into four groups: with CLP and ED (n=46), with CLP and without ED (n = 34), without CLP and with ED (n = 34), and without CLP or ED (n = 51). Genomic DNA was extracted from saliva followed by conducting a Polymerase Chain Reaction and direct DNA sequencing of exons 2 through 7 of AMELX. Mutations were found in 30% (n = 14), 35% (n = 12), 11% (n = 4) and 13% (n = 7) of the subjects from groups 1, 2, 3 and 4, respectively. Thirty seven mutations were detected and distributed throughout exons 2 (1 mutation - 2.7%), 6 (30 mutations - 81.08%) and 7 (6 mutations - 16.22%) of AMELX. No mutations were found in exons 3, 4 or 5. Of the 30 mutations found in exon 6, 43.34% (n = 13), 23.33% (n = 7), 13.33% (n = 4) and 20% (n = 6) were found in groups 1, 2, 3 and 4, respectively. c.261 C > T (rs2106416), a silent mutation, was detected in 26 subjects, and found more significantly (p = 0.003) in patients with CLP (groups 1 and 2 - 23.75%), compared with those without CLP (groups 3 and 4 - 8.23%). In the groups without ED, this silent mutation was also found more significantly (p = 0.032) among subjects with CLP (17.65% in group 2), compared with those without CLP (7.8% in group 4). In conclusion, this study suggested that AMELX may be a candidate gene for cleft lip and palate.

Background: Gene expression analysis of fibrosis-related genes may became useful for the early identification of fibrosis processes. We quantitatively assessed messenger RNA transcripts of the CTGF, TGF-β and KIM-1 genes, in biopsy samples from renal transplant recipients with graft dysfunction, to test the hypothesis that in patients with chronic disease of the renal transplant, these molecules could be markers of the development and severity of graft fibrosis., Methods: Ninety-six kidney transplant recipients who undertook 121 indication graft biopsies between January 2008 and December 2009 were included. Patients and biopsies were classified into 4 major diagnostic groups according to the Banff 2007 classification: acute tubular necrosis (ATN; n = 20), acute rejection (AR; n = 58), acute calcineurin inhibitor nephrotoxicity (CIN; n = 13) and interstitial fibrosis and tubular atrophy (IF/TA; n = 30)., Results: Messenger RNA transcripts of the CTGF and TGF-β genes were significantly higher in IF/TA compared with all other conditions. Messenger RNA transcripts of the KIM-1 gene in the IF/TA group were higher than in the CIN group. In addition, it was observed that gene expression of CTGF, TGF-β and KIM-1 increased with severity of fibrosis observed in the pathological examinations., Conclusions: Gene expression evaluation of the kidney graft tissue may be used to improve pathological diagnosis and perhaps for the future development of noninvasive biomarkers.

Background: To investigate gene expression of podocyte-specific proteins in urine of diabetes and prediabetes subjects and the association of these proteins with albuminuria., Methods: Fifteen controls, 19 prediabetes, and 67 diabetes subjects were included. Messenger RNA of nephrin, podocin, podocalyxin, synaptopodin, TRPC6, alpha-actinin-4, and TGF-β1 were measured using RT-PCR. Podocyte marker expression was correlated with albuminuria, glycemic control, and renal function. The diagnostic performance of the genes used to detect increased albuminuria was assessed using ROC curves and Poisson regressions., Results: Podocyte marker expression was significantly higher in diabetic subjects. Urinary nephrin was correlated with increasing levels of albuminuria; risk of albuminuria increased by 20% for every one-unit increase in the log10 of nephrin mRNA. Nephrinuria was found in 53%, 71%, and 90% of normo-, micro-, and macroalbuminuric diabetes subjects, respectively (p = 0.023). Urinary nephrin, podocalyxin, TRPC6, podocin, and alpha actinin-4 were correlated with glycemic control and albuminuria but not with renal function., Conclusions: Diabetes subjects had higher urinary mRNA levels of podocyte proteins than nondiabetic subjects, even the normoalbuminuric patients. Nephrinuria was correlated with diabetic nephrophathy stage and predicted pathological albuminuria. Urinary mRNA levels of podocyte markers of prediabetic subjects did not differ from controls.

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.

Patients on hemodialysis (HD) show changes in muscle structure and function reducing their functional capacity. This study was conduted to assess the effects of respiratory muscle training (RMT) and peripheral muscle training (PMT) during dialysis on functional parameters, inflammatory state, and quality of life (QoL) in patients on HD. Randomized controlled trial included 39 patients on HD, and they were divided into three groups: RMT (n = 11), PMT (n = 14), and controls (C, n = 14). Training was performed during the HD session for 10 weeks. Maximal inspiratory pressure (PI(max)), maximal expiratory pressure (PE(max)), forced vital capacity (FVC), six-minute walk test (6MWT), Kt/V(sp), biochemical parameters, and inflammatory state (i.e., level of high sensitivity C-reactive protein) were evaluated. Variation from baseline was calculated by Analysis of Covariance (ANCOVA). The ΔPI(max) was 22.5 ± 3.2, 9.1 ± 2.9, and -4.9 ± 2.8 cmH(2)O in the RMT, PMT and C, respectively (p < 0.001); ΔPE(max) was 10.8 ± 6.6, 3.7 ± 5.9, and -15.6 ± 5.9 cmH(2)O respectively (p = 0.014). The Δ6MWT was significantly greater in RMT and PMT (65.5 ± 9; 30.8 ± 8 m) than in C (-0.5 ± 8.1 m), p < 0.001. Although biochemical parameters decreased after training, Kt/V remained unchanged. CRP decreased only in the RMT and PMT groups. There was a significant increase in QoL scores in the training groups (vs. C) in energy/fatigue (p = 0.002), sleep (p < 0.001), pain (p < 0.001), and list of symptoms/problems (p = 0.014). A short period of RMT or PMT during HD significantly improved functional capacity, with RMT showing greater effect than PMT. Muscle training improved biochemical and inflammatory markers, but a direct cause and effect relationship could not be established by this study.

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.

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.

Naturally occurring and induced regulatory T cells (Tregs) can become hyporesponsive and anergic to antigen stimulation in autoimmune diseases and allograft rejection. The mechanisms of suppression of effector T cells by Tregs remain unclear, but there are in vitro and in vivo evidences showing that these cells are able to suppress antigen-specific responses via direct cell-to-cell contact, secrete anti-inflammatory cytokines such as TGF-β and IL-10, and inhibit the generation of memory T cells, among others. The transcription factor FOXP3 is a specific marker of Tregs and its deficiency is associated with autoimmune diseases and inflammation. During acute rejection of kidney allografts, an augmented FOXP3 gene expression as well as increased CD4(+)CD25(+)FOXP3(+) and other cell populations are observed in graft biopsies. However, it is not clear whether Tregs migrate into the graft and are retained there to suppress the inflammatory process, or whether they are directly associated with more complex mechanisms to induce immune tolerance. FOXP3(+) Tregs may direct the immune response toward a graft acceptance program, potentially affecting the long-term survival of transplanted organs and tissues. Immunosuppressive drugs modulate the number and function of circulating Tregs and FOXP3 expression. Experimental and clinical studies have shown that mTOR inhibitors have positive and calcineurin inhibitors negative effects on Tregs, but it is difficult to set apart the effect of multiple other factors known to be associated with short- and long-term renal graft outcomes. This review aimed to describe the functions of Tregs and its transcription factor FOXP3 in suppression of immune response during rejection and in induction of kidney graft tolerance, as well as to review the individual effects of immunosuppressive drugs on Tregs., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Introduction: Malnutrition is multifactorial and may be modified by nutritional intervention. We aimed to assess the impact of an intervention on the nutritional status of malnourished hemodialysis patients and their acceptance of a non-industrialized nutritional supplement., Methods: 18 patients were studied, they were selected from a previous nutritional assessment where nutritional risk was defined as: subjective global assessment > 15 plus one criterion for malnutrition. The following variables were assessed: anthropometric parameters, subjective global assessment, dietary intake, six-minute walking test, quality of life (SF-36), and biochemical tests. Patients were randomized to either Control or Intervention Groups. The Intervention Group received a dietetic supplement during dialysis containing 355 kcal, prepared from simple ingredients. After three months, subjects from the Control Group and other patients also considered at nutritional risk underwent the same intervention. The study groups were compared after three months, and all patients were analyzed before and after the intervention., Results: Fifteen men and three women, aged 56.4 ± 15.6 years-old, nine in each group, were studied. The Intervention Group showed an improvement in the subjective global assessment (p = 0.04). There were differences in role physical and bodily pain domains of SF-36, with improvement in the Intervention Group and worsening in the Control Group (p = 0.034 and p = 0.021). Comparisons before and after intervention for all patients showed improvement in the subjective global assessment (16.18 ± 4.27 versus 14.37 ± 4.20, p = 0.04), and in the six-minute walking test (496.60 ± 132.59 versus 547.80 ± 132.48 m; p = 0.036). The nutritional supplement was well tolerated by all patients, and it did not cause side effects., Conclusions: The nutritional intervention improved the subjective global assessment and quality of life of hemodialysis patients at short-term. A global intervention by a dietitian produced specific and nonspecific positive effects in the whole group. Nutritional supplementation was feasible, palatable, and had low cost. Its clinical impact and effectiveness need to be further assessed in a larger group of patients at long-term.

Introduction: C4d is a marker of antibody-mediated rejection (ABMR) in kidney allografts, although cellular rejection also have C4d deposits., Objective: To correlate C4d expression with clinico-pathological parameters and graft outcomes at three years., Methods: One hundred forty six renal transplantation recipients with graft biopsies by indication were included. C4d staining was performed by paraffin-immunohistochemistry. Graft function and survival were measured, and predictive variables of the outcome were determined by multivariate Cox regression., Results: C4d staining was detected in 48 (31%) biopsies, of which 23 (14.7%) had diffuse and 25 (16%) focal distribution. Pre-transplantation panel reactive antibodies (%PRA) class I and II were significantly higher in C4d positive patients as compared to those C4d negative. Both glomerulitis and pericapillaritis were associated to C4d (p = 0.002 and p < 0.001, respectively). The presence of C4d in biopsies diagnosed as no rejection (NR), acute cellular rejection (ACR) or interstitial fibrosis/ tubular atrophy (IF/TA) did not impact graft function or survival. Compared to NR, ACR and IF/TA C4d⁻, patients with ABMR C4d⁺ had the worst graft survival over 3 years (p = 0.034), but there was no difference between ABMR versus NR, ACR and IF/TA that were C4d positive (p = 0.10). In Cox regression, graft function at biopsy and high %PRA levels were predictors of graft loss., Conclusions: This study confirmed that C4d staining in kidney graft biopsies is a clinically useful marker of ABMR, with well defined clinical and pathological correlations. The impact of C4d deposition in other histologic diagnoses deserves further investigation.

Aims: To analyse the performances of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and of Modification of Diet in Renal Disease (MDRD) study equations to estimate glomerular filtration rate (GFR) in patients with Type 2 diabetes mellitus with GFRs >60 ml/min and in healthy volunteers., Methods: This cross-sectional study included 111 individuals (56 patients with Type 2 diabetes and 55 healthy volunteers), aged 58 ± 9 years; 54 individuals were men (49%) and ninety-eight (88%) were white. Glomerular filtration rate was measured by the (51) Cr-EDTA single-injection method ((51) Cr-GFR) and estimated according to the standardized MDRD and CKD-EPI equations. Serum creatinine was measured by a traceable Jaffe method. Bland-Altman analysis was used to examine the agreement between measured and estimated GFR. Bias, accuracy and precision were evaluated., Results: In diabetic individuals, (51) Cr-GFR was 106 ± 27 ml/min/1.73 m(2) , CKD-EPI-estimated GFR 82 ± 18 ml/min/1.73 m(2) and MDRD-estimated GFR 80 ± 21 ml/min/1.73 m(2) (P < 0.001). In healthy volunteers, the corresponding values were 98 ± 20, 89 ± 13 and 84 ± 14 ml/min/1.73 m(2) (P < 0.001). The accuracy of CKD-EPI (P30) was higher in healthy volunteers than in diabetic patients (90 vs. 66%, respectively, P < 0.001). The MDRD equation performed as poorly as the CKD-EPI equation in individuals with Type 2 diabetes., Conclusions: The CKD-EPI equation is less accurate in patients with Type 2 diabetes when compared with healthy individuals, with a 2.5-fold greater bias., (© 2010 The Authors. Diabetic Medicine © 2010 Diabetes UK.)

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.

Background: Inflammation and oxidative stress (OS) are risk factors for cardiovascular disease in chronic kidney disease (CKD). This study assessed the acute effect of simvastatin on inflammatory and OS markers in stage 3 and 4 CKD patients., Methods: Randomized, placebo-controlled, double-blind, cross-over study comprising 66 patients who were randomized to simvastatin (20 mg/day) or placebo for two 8-week periods. Glomerular filtration rate (GFR), lipid profile, C-reactive protein (CRP), fibrinogen, carbonyls and total radical-trapping antioxidant potential (TRAP) were measured. Interactions between potential confounding factors, such as diabetes mellitus, malnutrition, drug use, hypercholesterolemia and treatment response were assessed through the course of inflammatory and OS levels., Results: Thirty-three patients were randomized to simvastatin/placebo (S-P), and 33 to placebo/simvastatin (P-S). Simvastatin significantly reduced total and LDL cholesterol (pretreatment vs. posttreatment: p=0.0001 and p=0.0001, respectively) in both periods. No differences were seen in CRP, fibrinogen, carbonyls and TRAP levels between S-P and P-S groups at the end of the 2 study periods. GFR was similar in both groups and negatively correlated to fibrinogen (r=-0.25, p=0.04) and TRAP (r=-0.27, p=0.03). No interactions were found between confounding factors and response to simvastatin. There was no interference of either a period effect or any carryover effect on study results., Conclusions: The use of simvastatin in CKD patients acutely did not reduce serum inflammation or OS markers. Possibly higher doses and/or longer treatment course of statin are required to produce drug pleiotropic effects in nondialysis CKD patients.

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.

Continuous renal replacement therapies (CRRT) are commonly used in the majority of critically ill patients who need dialysis. Treatment success depends on an efficient anticoagulation protocol devised to maintain the dialysis circuit unclotted, with minimal complications such as bleeding due to excessive anticoagulation. Several features can contribute to dialysis circuit thrombosis, such as the speed of pump blood flow, dialysis catheter, type of dialyzer membrane and also, the type of technique prescribed. Unfractioned heparin (UFH) is the anticoagulant most used in CRRT. Recently, low-molecular weight heparins (LMWH) have been shown to be safe and effective drugs for this purpose. In critically ill patients, who frequently have contraindications to systemic anticoagulation, regional anticoagulation with trisodium citrate is an increasingly accepted method due to its safety and efficiency if applied under strict metabolic control. Regional anticoagulation with UFH/protamin now has limited use because of side effects related to protamin. If the patient has contraindication to systemic anticoagulation or if regional anticoagulation with citrate is not available, continuous flushing of circuit dialysis with saline is the only applicable alternative. In patients with contraindication to heparinization, new drugs not yet available in Brazil, such as prostaglandins, recombinant hirudin, argatroban and nafamostat can be used.

The Banff classification for kidney allograft pathology has proved to be reproducible, but its inter and intraobserver agreement can vary substantially among centres. The aim of this study was to evaluate Banff reproducibility of surveillance renal allograft biopsies among renal pathologists from different transplant centres. This study included 32 renal transplant patients with stable graft function. Biopsies were performed 2 and 12 months post-transplant. Histology was interpreted according to the Banff schema by three renal pathologists, and inter and intraobserver agreement were measured. The best reproducibility was obtained for the presence or absence of acute rejection (AR), with kappa values ranging from moderate (kappa = 0.47; p = 0.006) to good (kappa = 0.72; p = 0.0001). However, the agreement for 'suspicious for AR' category was poor between all observers. For scoring and grading interstitial inflammation and intimal arteritis the agreement were poor and moderate, respectively. Reproducibility for the presence or absence of chronic allograft nephropathy (CAN) was heterogeneous, ranging from poor (kappa = 0.13; p = NS) to moderate (kappa = 0.56; p = 0.007). Scoring chronic changes such as fibrous intimal thickening gave a reasonable interobserver agreement. Intraobserver reproducibility was good for presence or absence of AR, but was poor for the diagnosis of CAN. In conclusion, histologic analysis of stable renal allografts based on Banff criteria showed a good agreement for the diagnosis of AR and a reasonable kappa for CAN, but reproducibility for scoring and grading showed a substantial interobserver variation.

Subclinical acute rejection (SAR) occurs in about 30% of stable renal transplant patients and may be a risk factor for a poor allograft outcome. In the present study, the prevalence and clinical features of subclinical rejection, and the expression of immune activation markers in surveillance graft biopsies were assessed and correlated with late graft outcomes. Protocol biopsies were obtained at 2 and 12 months post-transplant in 32 and 26 patients, respectively, with stable renal function. The Banff 1997 criteria were used for histological diagnosis. Graft function and survival and proteinuria were assessed during the 36 months of follow-up. Immunohistochemical evaluation of cell subpopulations and immunoactivation markers were performed on protocol biopsies. The prevalence of SAR at 2 months and of chronic allograft nephropathy (CAN) at 12 months in representative biopsies was 55 and 50%, respectively. Patients with SAR presented mononuclear cell infiltration with an increased expression of CD3, CD4, CD68, IL-2R and granzyme B. Kidney graft function was significantly worse in patients with SAR at 2 months who had chronic rejection on biopsy at 12 months, but SAR was not associated with a worse graft function, greater proteinuria or a lower graft survival in 3 yr of follow-up. In conclusion, we found an elevated prevalence of SAR at 2 months after transplantation with an increased expression of activation markers. Although an association of SAR with poor graft outcome was not observed, our results suggest that SAR is an immunologically active process and underscore the importance of protocol biopsies in the surveillance of transplanted kidneys.