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.

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.

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.

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.

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.

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.

Força muscular respiratória e capacidade funcional em pacientes com doença renal crônica / Respiratory muscle force and functional capacity in patients with chronic kidney disease

A Doença Renal Crônica (DRC) é caracterizada pela perda progressiva, irreversível e multifatorial da função renal que pode desencadear alterações nos diversos sistemas do organismo. A progressão da DRC leva ao desenvolvimento da miopatiaurêmica, que se caracteriza pela perda de músculos e redução da capacidade física. O presente estudo objetiva avaliar a força muscular respiratória e a capacidade funcional, bem como a relação entre os valores preditos e obtidos em pacientes com DRC submetidos a hemodiálise. A amostra foi composta por 17 pacientes com diagnóstico de DRC (com média de idade de 54,1±14,1 anos, massa de 64,2±11,8 kg, estatura 161,3±8,1 e índice de massa corporal (IMC) de 24,5±3,1 kg/m²) em acompanhamento no Hospital de Clínicas de Porto Alegre HCPA (CAAE 36473714.1.0000.5327). A funcionalidade dos pacientes foi avaliada pelo teste de caminhada de 6 minutos (TC6') e a força muscular respiratória através da manovacuometria. O tempo médio de tratamento em hemodiálise (THD) foi de 72,38±41,62 meses. A pressão inspiratória máxima (PI_máx) obtida foi menor que a PI_máx predita (71,5±25,5; 97,7±11 cm H2O; p=0,000), no entanto, não houve diferença entre a pressão expiratória máxima (PE_máx) obtida e a predita (100,53±36,56; 102,29±14,87 11 cm H2O; p= 0,474). Não foram encontradas correlações estatisticamente significativas entre as variáveis pulmonares e o TC6' e nem com o THD. Sugere-se que os pacientes com DRC desse estudo possuem fraqueza muscular inspiratória, no entanto, não foi encontrada relação entre a força muscular respiratória com a funcionalidade e com o tempo de hemodiálise.

Chronic Kidney Disease (CKD) is characterized by the progressive, irreversible and multifactorial loss of kidney function that can trigger changes in the various systems of the body. The progression of CKD leads to the development of uremic myopathy, characterized by muscle loss and reduced physical capacity. This study aims at evaluating respiratory muscle strength and functional capacity, as well as the relationship between predicted and obtained values in patients with CKD undergoing hemodialysis. The sample consisted of 17 patients with a diagnosis of CKD (mean age 54.1 ± 14.1 years, body mass of 64.2 ± 11.8 kg, height 161.3 ± 8.1 and body mass index (BMI) of 24.5 ± 3.1 kg / m²) under follow-up at the Hospital de Clínicas de Porto Alegre HCPA (CAAE 36473714.1.0000.5327). The patients' functionality was assessed by the 6-minute walk test (6MWT) and respiratory muscle strength through manovacuometry test. The mean treatment time on hemodialysis (THD) was 72.38 ± 41.62 months. The maximal inspiratory pressure (PI_max) obtained was lower than the predicted PI_max (71.5 ± 25.5, 97.7 ± 11 cm H2O, p = 0.000). However, there was no difference between the maximum expiratory pressure (PE_max) obtained and predicted (100.53 ± 36.56, 102.29 ± 14.87 11 cm H2O, p = 0.474). No statistically significant correlations were found between the pulmonary variables and the 6MWT nor the THD. It is suggested that patients with CKD in this study have inspiratory muscle weakness; however, no relationship was found between respiratory muscle strength and time and function of hemodialysis.

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.

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.

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.

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.

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.

A Phase 2, Double-Blind, Placebo-Controlled, Randomized Study of Fresolimumab in Patients With Steroid-Resistant Primary Focal Segmental Glomerulosclerosis.

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-ß 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 m2 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.

Muscle thickness of the pectoralis major and rectus abdominis and level of physical activity in chronic hemodialysis patients / Espessura muscular do pectoralis major e do rectus abdominis e nível de atividade física em pacientes em hemodiálise crônica

Abstract 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.

Resumo Introdução: Pacientes que realizam hemodiálise crônica tendem a perder massa magra e ter comportamento sedentário. Objetivo: Comparar o nível de atividade física e morfologia dos músculos peitoral maior e reto do abdômen de pacientes que realizam hemodiálise com indivíduos saudáveis. Métodos: Foram estudados 17 pacientes e 17 indivíduos saudáveis. As espessuras musculares foram avaliadas por meio de ultrassonografia, e o nível de atividade física pelo Questionário Internacional de Atividade Física versão longa (IPAQ). Resultados: Os pacientes apresentaram menores espessuras do peitoral maior (5,92 ± 0,35 mm vs. 8,35 ± 0,62 mm, p < 0,001) e de reto abdominal (0,96 ± 0,10 mm vs. 2,21 ± 0,40 mm, p < 0,001) comparados aos sujeitos saudáveis. Os pacientes foram fisicamente menos ativos que os indivíduos saudáveis: 1502.55(788.19-2513.00) MET-minutos/semana vs. 2268.0(1680.0-4490,8) MET-minutos/semana (p = 0,006); o gasto calórico semanal dos pacientes também foi menor: 1384,0(480,7-2253.7) kcal/kg/semana vs. 1680,0(1677,4-4950,0) kcal/kg/semana (p = 0,010). O tempo médio gasto sentado por semana dos pacientes foi maior que dos sujeitos saudáveis (394,0 ± 33,1 min/dia vs. 293,0 ± 38,6, p = 0,009), assim como o tempo médio gasto sentado durante o fim de semana (460,0 ± 40,1 vs. 201,0 ± 10,7, p = 0,003). Conclusão: Pacientes renais crônicos em hemodiálise apresentam comportamento sedentário e menores espessuras musculares do tronco.

Acute effects of intradialytic aerobic exercise on solute removal, blood gases and oxidative stress in patients with chronic kidney disease / Efeitos agudos do exercício aeróbio intradialítico sobre a remoção de solutos, gasometria e estresse oxidativo em pacientes com doença renal crônica

Abstract 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.

Resumo Introdução: A hemodiálise contribui para aumentar o estresse oxidativo e induz a hipoxemia transitória. A compartimentalização dos solutos diminui sua oferta para o dialisador durante o tratamento. O objetivo deste estudo foi investigar os efeitos agudos do exercício aeróbio intradialítico sobre a remoção de solutos, gasometria e estresse oxidativo em pacientes com doença renal crônica durante uma sessão de hemodiálise. Métodos: Trinta pacientes foram randomizados para realizar exercício aeróbio com cicloergômetro para membros inferiores durante 30 minutos com intensidade entre 60-70% da frequência cardíaca máxima, ou grupo controle (GC). Amostras sanguíneas foram coletadas antes e imediatamente após o término do exercício ou no período equivalente no GC. Análises da bioquímica do sangue e dialisato e gasometria foram realizadas. A massa removida e a depuração dos solutos foram calculadas. O estresse oxidativo foi determinado pela peroxidação lipídica e capacidade antioxidante total. Resultados: As concentrações séricas dos solutos aumentaram com o exercício, mas somente o fósforo mostrou elevação significativa (p = 0.035). Não houve modificações significantes na remoção de solutos e no equilíbrio ácido-básico. A pressão parcial e a saturação de oxigênio aumentaram com o exercício (p = 0.035 e p = 0.024, respectivamente), o que não ocorreu no GC. A capacidade antioxidante total diminuiu significativamente (p = 0.027). Conclusão: O exercício aeróbico intradialítico agudo aumentou a concentração sérica de fósforo e diminuiu a capacidade antioxidante total, revertendo a hipoxemia resultante da hemodiálise. O exercício intradialítico não alterou o equilíbrio ácido-básico e a remoção de solutos.

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.

Unraveling the podocyte injury in lupus nephritis: Clinical and experimental approaches.

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.

Muscle thickness of the pectoralis major and rectus abdominis and level of physical activity in chronic hemodialysis patients.

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.

Acute tubulointerstitial nephritis with severe renal impairment associated with multisystem IgG4-related disease.

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.