Hipertensão pulmonar em pacientes com doença renal crônica dialítica está associada com hipervolemia e inflação

Pós-graduação em Fisiopatologia em Clínica Médica - FMB

Proteinuria predicts relapse in adolescent and adult minimal change disease

OBJECTIVE: This study sought to outline the clinical and laboratory characteristics of minimal change disease in adolescents and adults and establish the clinical and laboratory characteristics of relapsing and non-relapsing patients. METHODS: We retrospectively evaluated patients with confirmed diagnoses of minimal change disease by renal biopsy from 1979 to 2009; the patients were aged >13 years and had minimum 1-year follow-ups. RESULTS: Sixty-three patients with a median age (at diagnosis) of 34 (23-49) years were studied, including 23 males and 40 females. At diagnosis, eight (12.7%) patients presented with microscopic hematuria, 17 (27%) with hypertension and 17 (27%) with acute kidney injury. After the initial treatment, 55 (87.3%) patients showed complete remission, six (9.5%) showed partial remission and two (3.1%) were nonresponders. Disease relapse was observed in 34 (54%) patients who were initial responders (n = 61). In a comparison between the relapsing patients (n = 34) and the non-relapsing patients (n = 27), only proteinuria at diagnosis showed any significant difference (8.8 (7.1-12.0) vs. 6.0 (3.6-7.3) g/day, respectively, p = 0.001). Proteinuria greater than 7 g/day at the initial screening was associated with relapsing disease. CONCLUSIONS: In conclusion, minimal change disease in adults may sometimes present concurrently with hematuria, hypertension, and acute kidney injury. The relapsing pattern in our patients was associated with basal proteinuria over 7 g/day.

Prevalence of adults with type 1 diabetes who meet the goals of care in daily clinical practice: A nationwide multicenter study in Brazil

Objective: To determine the prevalence of patients with type 1 diabetes mellitus who meet the glycemic and cardiovascular (CV) risk factors goals and the frequency of screening for diabetic complications in Brazil according to the American Diabetes Association guidelines. Research design and methods: This was a cross-sectional, multicenter study conducted between December 2008 and December 2010 in 28 public clinics in 20 Brazilian cities. Data were obtained from 1774 adult patients (56.8% females, 57.2% Caucasians) aged 30.3 +/- 9.8 years with diabetes duration of 14.3 +/- 8.8 years. Results: Systolic blood pressure was at goal in 40.3% and diastolic blood pressure was at goal in 26.6% of hypertensive patients. LDL cholesterol and HbA1c were at the goal in 45.2% and 13.2% of the patients, respectively. Overweight was presented in 25.6% and obesity in 6.9%. Among those with more than 5 years of disease, screening for retinopathy was performed in the preceding year in 70.1%. Nephropathy and feet complications were screened in 63.1% and 65.1%, respectively. Conclusions: The majority of patients did not meet metabolic control goals and a substantial proportion was not screened for diabetic complications. These issues may increase the risk of chronic complications and negatively impact public health. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

Multicentric Carpotarsal Osteolysis Is Caused by Mutations Clustering in the Amino-Terminal Transcriptional Activation Domain of MAFB

Multicentric carpotarsal osteolysis (MCTO) is a rare skeletal dysplasia characterized by aggressive osteolysis, particularly affecting the carpal and tarsal bones, and is frequently associated with progressive renal failure. Using exome capture and next-generation sequencing in five unrelated simplex cases of MCTO, we identified previously unreported missense mutations clustering within a 51 base pair region of the single exon of MAFB, validated by Sanger sequencing. A further six unrelated simplex cases with MCTO were also heterozygous for previously unreported mutations within this same region, as were affected members of two families with autosomal-dominant MCTO. MAFB encodes a transcription factor that negatively regulates RANKL-induced osteoclastogenesis and is essential for normal renal development. Identification of this gene paves the way for development of novel therapeutic approaches for this crippling disease and provides insight into normal bone and kidney development.

Antifibrotic Effect of Tamoxifen in a Model of Progressive Renal Disease

Tamoxifen, a selective estrogen receptor modulator, has antifibrotic properties; however, whether it can attenuate renal fibrosis is unknown. In this study, we tested the effects of tamoxifen in a model of hypertensive nephrosclerosis (chronic inhibition of nitric oxide synthesis with L-NAME). After 30 days, treated rats had significantly lower levels of albuminuria as well as lower histologic scores for glomerulosclerosis and interstitial fibrosis than untreated controls. Tamoxifen was renoprotective despite having no effect on the sustained, severe hypertension induced by L-NAME. Tamoxifen prevented the accumulation of extracellular matrix by decreasing the expression of collagen I, collagen III, and fibronectin mRNA and protein. These renoprotective effects associated with inhibition of TGF-beta 1 and plasminogen activator inhibitor-1, and with a significant reduction in a-smooth muscle actin-positive cells in the renal interstitium. Furthermore, tamoxifen abrogated IL-1 beta- and angiotensin-II-induced proliferation of fibroblasts from both kidney explants and from the NRK-49F cell line. Tamoxifen also inhibited the expression of extracellular matrix components and the production and release of TGF-beta 1 into the supernatant of these cells. In summary, tamoxifen exhibits antifibrotic effects in the L-NAME model of hypertensive nephrosclerosis, likely through the inhibition of TGF-beta 1, suggesting that it may have therapeutic use in CKD treatment.

Increased TLR2 expression in patients with type 1 diabetes: evidenced risk of microalbuminuria

Objective: To study the activation of an inflammatory cascade through leukocyte mRNA expression of TLR2, TLR4, MyD88, and pro-inflammatory cytokines in individuals with childhood onset type 1 diabetes. Design and methods: Seventy-six type 1 diabetic patients and 100 normoglycemic subjects (NG) 6 to 20 years old were recruited. Type 1 diabetic patients (DM1) were considered to have good (DM1G) or poor (DM1P) glycemic control according to the values of glycated hemoglobin. TLR2, TLR4, MyD88, interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor alpha (TNF-alpha) mRNA expressions were measured in peripheral blood leukocytes (PBL) by real-time polymerase chain reaction (PCR). Urea, creatinine, albumin, and total protein serum levels were determined. Urinary albumin-to-creatinine ratio (ACR) was calculated. Results: DM1 and DM1P patients showed higher glycated hemoglobin (10 and 11%, respectively) and serum glucose concentrations (208 and 226 mg/ dL, respectively) compared to NG (Glycated hemoglobin: 7% and glucose: 76 mg/ dL) (p < 0.05). PBL mRNA expressions of TLR2, MyD88, IL-1 beta, IL-6, and TNF-alpha were higher in DM1 and TLR2, IL-1 beta, and IL-6 expressions were higher in DMP1 compared to NG (p < 0.05). In DM1, serum albumin and total protein were lower, while serum urea and ACR were higher in comparison to NG (p < 0.05). However, these differences compared to NG were more pronounced in DM1P, which included nine individuals with microalbuminuria. Conclusions: Increased mRNA expression of TLR2, MyD88, and pro-inflammatory cytokines in leukocytes of patients with childhood onset type 1 diabetes indicates the development of a TLR2-mediated pro-inflammatory process, which may also be associated with an early inflammatory process in the kidney and the occurrence of microalbuminuria.

Surgical Treatment of Type 2 Diabetes in Patients with BMI Below 35: Mid-term Outcomes of the Laparoscopic Ileal Interposition Associated with a Sleeve Gastrectomy in 202 Consecutive Cases

The objective of this study was to evaluate the mid-term outcomes of the laparoscopic ileal interposition into the jejunum (JII-SG) or into the duodenum (DII-SG) associated with sleeve gastrectomy for type 2 diabetes mellitus (T2DM) patients with BMI below 35. The procedures were performed on 202 consecutive patients. Mean age was 52.2 +/- 7.5. Mean duration of T2DM was 9.8 +/- 5.2 years. Insulin therapy was used by 41.1%. Dyslipidemia was observed in 78.2%, hypertension in 67.3%, nephropathy in 49.5%, retinopathy in 31.2%, coronary heart disease in 11.9%, and other cardiovascular events in 12.9%. Mean follow-up was 39.1 months (range, 25-61). Early and late mortality was 0.99% and 1.0%, respectively. Early reoperation was performed in 2.5%. Early and late major complications were 8.4% and 3.5%. Early most frequent complications were pneumonia and ileus. Intestinal obstruction was diagnosed in 1.5%. Mean BMI decreased from 29.7 to 23.5 kg/m(2), mean fasting glucose from 202.1 to 112.2 mg/dl, and mean postprandial glucose from 263.3 to 130 mg/dl. Triglycerides diminished from a mean of 273.4 to 110.3 mg/dl and cholesterol from a mean of 204.7 to 160.1 mg/dl. Hypertension was resolved in 87.5%. Mean hemoglobin A(1c) (HbA(1c)) decreased from 8.7 to 6.2% after the JII-SG and to 5.9% following the DII-SG. HbA(1c) below 7% was seen in 89.9% of the patients and below 6.5% in 78.3%. Overall, 86.4% of patients were off antidiabetic medications. Both JII-SG and DII-SG demonstrated to be safe, effective, and long-lasting alternatives for the treatment of T2DM patients with BMI < 35. Beyond glycemic control, other benefits were achieved.

Previous Exposure to Cigarette Smoke Aggravates Experimental Cyclosporine-Induced Nephrotoxicity

Background/Aims: The effects of cigarette smoke (CS) on cyclosporine (CsA)-induced nephrotoxicity are poorly studied. This study aims to assess the effects of previous exposure to CS on CsA nephrotoxicity. Methods: Rats were either exposed to CS or sham (S) procedures for 10 min twice a day for 20 weeks. From the 16th to the 20th week, they received a low-salt diet. Beginning with the 17th week, they were given 2.5 mg/day CsA or vehicle (VH) for 3 weeks. The final groups were VH/CS, CsA/CS, VH/S, and CsA/S. On day 141, glomerular filtration rate (GFR), renal blood flow (RBF), renal vascular resistance (RVR), tubulointerstitial fibrosis, and CsA blood levels were measured and immunohistochemistry was analyzed for renal alpha-smooth muscle actin (SMA), nitrotyrosine, and vimentin. Results: CsA decrease in GFR was enhanced by CS exposure. CsA associated with CS induced higher periglomerular alpha-SMA and renal nitrotyrosine expression. CsA decreased RBF, but increased RVR, tubulointerstitial fibrosis, and alpha-SMA and renal vimentin expression. These changes and the CsA blood levels were not affected by CS exposure. Conclusion: CS aggravated the CsA-induced impairment of GFR and CS associated with CsA caused the development of periglomerular structural lesions and oxidative stress in a rat model of CsA nephrotoxicity. Copyright (C) 2012 S. Karger AG, Basel

Low-Level Laser Therapy Decreases Renal Interstitial Fibrosis

Objective: the purpose of this study was to investigate the effect of low-level laser therapy (LLLT) on chronic kidney disease (CKD) in a model of unilateral ureteral obstruction (UUO). Background data: Regardless of the etiology, CKD involves progressive widespread tissue fibrosis, tubular atrophy, and loss of kidney function. This process also occurs in kidney allograft. At present, effective therapies for this condition are lacking. We investigated the effects of LLLT on the interstitial fibrosis that occurs after experimental UUO in rats. Methods: The occluded kidney of half of the 32 Wistar rats that underwent UUO received a single intraoperative dose of LLLT (AlGaAs laser, 780 nm, 22.5 J/cm(2), 30mW, 0.75W/cm(2), 30 sec on each of nine points). After 14 days, renal fibrosis was assessed by Sirius red staining under polarized light. Immunohistochemical analyses quantitated the renal tissue cells that expressed fibroblast (FSP-1) and myofibroblast (alpha-SMA) markers. Reverse transcriptase polymerase chain reaction (RT-PCR) was performed to determine the mRNA expression of interleukin (IL)-6, monocyte chemotactic protein-1 (MCP-1), transforming growth factor (TGF)-beta 1 and Smad3. Results: The UUO and LLLT animals had less fibrosis than the UUO animals, as well having decreased expression inflammatory and pro-fibrotic markers. Conclusions: For the first time, we showed that LLLT had a protective effect regarding renal interstitial fibrosis. It is conceivable that by attenuating inflammation, LLLT can prevent tubular activation and transdifferentiation, which are the two processes that mainly drive the renal fibrosis of the UUO model.

Minimal change disease associated with type 1 and type 2 diabetes mellitus

A 19-year-old female with type 1 diabetes for four years, and a 73-year-old female with type 2 diabetes for twenty years developed sudden-onset nephrotic syndrome. Examination by light microscopy, immunofluorescence, and electron microscopy (in one case) identified minimal change disease (MCD) in both cases. There was a potential causative drug (meloxicam) for the 73-year-old patient. Both patients were treated with prednisone and responded with complete remission. The patient with type 1 diabetes showed complete remission without relapse, and the patient with type 2 diabetes had two relapses; complete remission was sustained after associated treatment with cyclophosphamide and prednisone. Both patients had two years of follow-up evaluation after remission. We discuss the outcomes of both patients and emphasize the role of kidney biopsy in diabetic patients with an atypical proteinuric clinical course, because patients with MCD clearly respond to corticotherapy alone or in conjunction with other immunosuppressive agents. Arq Bras Endocrinol Metab. 2012;56(5):331-5

MyD88 Signaling Pathway Is Involved in Renal Fibrosis by Favoring a T(H)2 Immune Response and Activating Alternative M2 Macrophages

Inflammation contributes to the pathogenesis of chronic kidney disease (CKD). Molecules released by the inflamed injured tissue can activate toll-like receptors (TLRs), thereby modulating macrophage and CD4+ T-cell activity. We propose that in renal fibrogenesis, M2 macrophages are recruited and activated in a T helper subset 2 cell (TH2)-prone inflammatory milieu in a MyD88- dependent manner. Mice submitted to unilateral ureteral ligation (UUO) demonstrated an increase in macrophage infiltration with collagen deposition after 7 d. Conversely, TLR2, TLR4 and MyD88 knockout (KO) mice had an improved renal function together with diminished TH2 cytokine production and decreased fibrosis formation. Moreover, TLR2, TLR4 and MyD88 KO animals exhibited less M2 macrophage infiltration, namely interleukin (IL)-10+ and CD206+ CD11bhigh cells, at 7 d after surgery. We evaluated the role of a TH2 cytokine in this context, and observed that the absence of IL-4 was associated with better renal function, decreased IL-13 and TGF- β levels, reduced arginase activity and a decrease in fibrosis formation when compared with IL-12 KO and wild-type (WT) animals. Indeed, the better renal outcomes and the decreased fibrosis formation were restricted to the deficiency of IL-4 in the hematopoietic compartment. Finally, macrophage depletion, rather than the absence of T cells, led to reduced lesions of the glomerular filtration barrier and decreased collagen deposition. These results provide evidence that future therapeutic strategies against renal fibrosis should be accompanied by the modulation of the M1:M2 and TH1:TH2 balance, as TH2 and M2 cells are predictive of fibrosis toward mechanisms that are sensed by innate immune response and triggered in a MyD88-dependent pathway.

Both XPA and DNA polymerase eta are necessary for the repair of doxorubicin-induced DNA lesions

Doxorubicin (DOX) is an important tumor chemotherapeutic agent, acting mainly by genotoxic action. This work focus on cell processes that help cell survival, after DOX-induced DNA damage. In fact, cells deficient for XPA or DNA polymerase eta (pol eta, XPV) proteins (involved in distinct DNA repair pathways) are highly DOX-sensitive. Moreover, LY294002, an inhibitor of PIKK kinases, showed a synergistic killing effect in cells deficient in these proteins, with a strong induction of G2/M cell cycle arrest. Taken together, these results indicate that XPA and pol eta proteins participate in cell resistance to DOX-treatment, and kinase inhibitors can selectively enhance its killing effects, probably reducing the cell ability to recover from breaks induced in DNA. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

Annexin A1 protein attenuates cyclosporine-induced renal hemodynamics changes and macrophage infiltration in rats

Cyclosporine (CsA) remains an important immunosuppressant for transplantation and for treatment of autoimmune diseases. The most troublesome side effect of CsA is renal injury. Acute CsA-induced nephrotoxicity is characterized by reduced renal blood flow (RBF) and glomerular filtration rate (GFR) due to afferent arteriole vasoconstriction. Annexin A1 (ANXA1) is a potent anti-inflammatory protein with protective effect in renal ischemia/reperfusion injury. Here we study the effects of ANXA1 treatment in an experimental model of acute CsA nephrotoxicity. Salt-depleted rats were randomized to treatment with VH (vehicles 1 mL/kg body weight/day), ANXA1 (Ac2-26 peptide 1 mg/kg body weight/day intraperitoneally), CsA (20 mg/kg body weight/day subcutaneously) and CsA + ANXA1 (combination) for seven days. We compared renal function and hemodynamics, renal histopathology, renal tissue macrophage infiltration and renal ANXA1 expression between the four groups. CsA significantly impaired GFR and RBF, caused tubular dilation and macrophage infiltration and increased ANXA1 renal tissue expression. Treatment with ANXA1 attenuated CSA-induced hemodynamic changes, tubular injury and macrophage infiltration. ANXA1 treatment attenuated renal hemodynamic injury and inflammation in an acute CsA nephrotoxicity model.

Co-nanoencapsulation of magnetic nanoparticles and selol for breast tumor treatment: in vitro evaluation of cytotoxicity and magnetohyperthermia efficacy

Antitumor activities have been described in selol, a hydrophobic mixture of molecules containing selenium in their structure, and also in maghemite magnetic nanoparticles (MNPs). Both selol and MNPs were co-encapsulated within poly(lactic-co-glycolic acid) (PLGA) nanocapsules for therapeutic purposes. The PLGA-nanocapsules loaded with MNPs and selol were labeled MSE-NC and characterized by transmission and scanning electron microscopy, electrophoretic mobility, photon correlation spectroscopy, presenting a monodisperse profile, and positive charge. The antitumor effect of MSE-NC was evaluated using normal (MCF-10A) and neoplastic (4T1 and MCF-7) breast cell lines. Nanocapsules containing only MNPs or selol were used as control. MTT assay showed that the cytotoxicity induced by MSE-NC was dose and time dependent. Normal cells were less affected than tumor cells. Cell death occurred mainly by apoptosis. Further exposure of MSE-NC treated neoplastic breast cells to an alternating magnetic field increased the antitumor effect of MSE-NC. It was concluded that selol-loaded magnetic PLGA-nanocapsules (MSE-NC) represent an effective magnetic material platform to promote magnetohyperthermia and thus a potential system for antitumor therapy.

N-Acetylcysteine Protects Rats with Chronic Renal Failure from Gadolinium-Chelate Nephrotoxicity

The aim of this study was to evaluate the effect of Gd-chelate on renal function, iron parameters and oxidative stress in rats with CRF and a possible protective effect of the antioxidant N-Acetylcysteine (NAC). Male Wistar rats were submitted to 5/6 nephrectomy (Nx) to induced CRF. An ionic - cyclic Gd (Gadoterate Meglumine) was administrated (1.5 mM/KgBW, intravenously) 21 days after Nx. Clearance studies were performed in 4 groups of anesthetized animals 48 hours following Gd-chelate administration: 1 - Nx (n = 7); 2 - Nx+NAC (n = 6); 3 - Nx+Gd (n = 7); 4 - Nx+NAC+Gd (4.8 g/L in drinking water), initiated 2 days before Gd-chelate administration and maintained during 4 days (n = 6). This group was compared with a control. We measured glomerular filtration rate, GFR (inulin clearance, ml/min/kg BW), proteinuria (mg/24 hs), serum iron (mu g/dL); serum ferritin (ng/mL); transferrin saturation (%), TIBC (mu g/dL) and TBARS (nmles/ml). Normal rats treated with the same dose of Gd-chelate presented similar GFR and proteinuria when compared with normal controls, indicating that at this dose Gd-chelate is not nephrotoxic to normal rats. Gd-chelate administration to Nx-rats results in a decrease of GFR and increased proteinuria associated with a decrease in TIBC, elevation of ferritin serum levels, transferrin oversaturation and plasmatic TBARS compared with Nx-rats. The prophylactic treatment with NAC reversed the decrease in GFR and the increase in proteinuria and all alterations in iron parameters and TBARS induced by Gd-chelate. NAC administration to Nx rat did not modify the inulin clearance and iron kinetics, indicating that the ameliorating effect of NAC was specific to Gd-chelate. These results suggest that NAC can prevent Gd-chelate nephrotoxicity in patients with chronic renal failure.