15 research outputs found

    Regression of advanced diabetic nephropathy by hepatocyte growth factor gene therapy in rats

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    Diabetic nephropathy is the main cause of end-stage renal disease requiring dialysis in developed countries. In this study, we demonstrated the therapeutic effect of hepatocyte growth factor (HGF) on advanced rather than early diabetic nephropathy using a rat model of streptozotocin-induced diabetes. Early diabetic nephropathy (16 weeks after induction of diabetes) was characterized by albuminuria, hyperfiltration, and glomerular hypertrophy, whereas advanced diabetic nephropathy showed prominent transforming growth factor (TGF)-beta1 upregulation, mesangial expansion, and glomerulosclerosis. An SP1017-formulated human HGF (hHGF) plasmid was administered by intramuscular injection combined with electroporation over a 30-day follow-up in rats with early and advanced diabetic nephropathy. hHGF gene therapy upregulated endogenous rat HGF in the diabetic kidney (rat HGF by RT-PCR was threefold higher than in diabetic rats without therapy). hHGF gene therapy did not improve functional or morphologic abnormalities in early diabetic nephropathy. hHGF gene therapy reduced albuminuria and induced strong regression of mesangial expansion and glomerulosclerosis in advanced diabetic nephropathy. These findings were associated with suppression of renal TGF-beta1 and mesangial connective tissue growth factor (CTGF) upregulation, inhibition of renal tissue inhibitor of metalloproteinase (TIMP)-1 expression, and reduction of renal interstitial myofibroblasts. In conclusion, our results suggest that hHGF gene therapy may be considered as an innovative therapeutic strategy to treat advanced diabetic nephropathy

    Adaptación glomerular en el trasplante renal evaluada mediante biopsias de protocolo

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    [spa] INTRODUCCIÓN: La nefropatía crónica del trasplante (NCT) es el principal predictor de evolución del injerto a largo plazo. Algunas características clínicas e histológicas propias de esta entidad son típicas respuestas a la reducción de masa nefronal, que puede tener consecuencias tan graves sobre el injerto como la presencia de isquemia fría prolongada o la discrepancia en el HLA. Brenner propone que la relación masa renal/peso receptor (Kw/Bw) refleja una relación entre el "aporte renal" y la demanda metabólica total. El número total de glomérulos en sujetos normales muestra una variabilidad muy importante, entre 0,2 y 1,8 x 106 por riñón. Esta información cuantitativa proviene de estudios de riñones completos provenientes de autopsias, a través del uso de técnicas que evalúan la diferente densidad de los glomérulos en la corteza renal, o con técnicas histomorfométricas. Cuando la masa renal disminuye, las nefronas remanentes adaptan su estructura y función para hacer frente a una mayor demanda metabólica. Sin embargo, la hipertrofia glomerular y los cambios hemodinámicos que ocurren en el glomérulo inician y perpetúan la injuria glomerular. La glomerulomegalia es un marcador de riesgo en pacientes con enfermedad renal o en determinadas poblaciones para la progresión de enfermedad. El grupo de Bhathena observó en grupos con glomeruloesclerosis focal y segmentaria que el diámetro glomerular medio de los pacientes trasplantados renales era significativamente menor que el de otros grupos con riñones nativos (p<0,01). Esto indica que el umbral para el desarrollo de esclerosis glomerular en trasplantados renales es mucho más bajo que en otros estados nefronopénicos. Existen evidencias de que el volumen glomerular (Vg) basal del donante es un predictor independiente temprano de evolución del injerto. También la medida del volumen intersticial en biopsias de donante ha demostrado su utilidad para predecir la función renal en el receptor. A partir de biopsias de protocolo, y con ayuda de resonancia magnética, se ha podido estimar el número de glomérulos (Ng) en una población estable de trasplantados renales. En este estudio, se observó que la edad del donante correlacionaba positivamente con el Vg y negativamente con el Ng. Más recientemente, se ha descrito la utilidad del índice de resistencia (IR) renal medido por Doppler como predictor de supervivencia del injerto. A pesar de la existencia de todas las evidencias presentadas, no había hasta el momento estudios que evaluaran la adaptación glomerular en trasplantados renales con biopsias pareadas de donante y receptor, ni se conocía la utilidad del Vg como predictor de supervivencia del injerto. OBJETIVOS: 1. Evaluar la evolución del Vg en los primeros 4 meses después del trasplante renal. 2. Evaluar la asociación entre el crecimiento glomerular y variables clínicas y demográficas. 3. Evaluar la asociación entre crecimiento glomerular y presencia de lesiones histológicas evaluadas mediante la clasificación de Banff. 4. Determinar la relación entre el Vg determinado en la biopsia de protocolo y la función y supervivencia del injerto. 5. Analizar la relación entre los datos clínicos e histológicos con la supervivencia del injerto. 6. Analizar si hay relación entre IR del injerto renal y otros predictores de supervivencia del injerto como Vg. PUBLICACIONES: 1. "Glomerular enlargement assessed by paired donor and early protocol renal allograft biopsies". G. Alperovich, R. Maldonado, F. Moreso, X. Fulladosa, JM. Grinyó, D. Serón. Am J Transplant. 2004, 4: 650-654. IF: 5.678 2. "Glomerular size in early protocol biopsies is associated with graft outcome". F. Azevedo, G. Alperovich, F. Moreso, M. Ibernon, M. Gomà, X. Fulladosa, M. Hueso, M. Carrera, JM. Grinyó, D. Serón. Am J Transplant. 2005, 5: 2877-2882. IF: 5.678 3. "Resistive index and chronic allograft nephropathy evaluated in protocol biopsies as predictors of graft outcome". A. Vallejos, G. Alperovich, F. Moreso, C. Cañas, ME de Lama, M. Gomá, X. Fulladosa, M. Carrera, M. Hueso, JM. Grinyó, D. Serón. Nephrol Dial Transplant. 2005, 20: 2511-2516.IF: 2.8

    Efficacy, safety, usability, and acceptability of risankizumab 150 mg formulation administered by prefilled syringe or by an autoinjector for moderate to severe plaque psoriasis

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    Background Risankizumab is approved for treatment of moderate to severe plaque psoriasis. Availability of a patient-controlled single self-injection of risankizumab may improve adherence and long-term management of psoriasis. Objective To investigate efficacy, safety, and usability of a new risankizumab 150 mg/mL formulation administered as a single subcutaneous injection via prefilled syringe (PFS) or autoinjector (AI). Methods Efficacy, safety, usability, and acceptability of risankizumab 150 mg/mL PFS or AI were investigated in adults with moderate to severe psoriasis in two phase 3 studies. Study 1 was a multicenter, randomized, double-blinded, placebo-controlled study that investigated 150 mg/mL risankizumab PFS; study 2 was a multicenter, single-arm, open-label study that investigated 150 mg/mL risankizumab AI. Results At week 16, risankizumab 150 mg/mL demonstrated efficacy vs. placebo (Psoriasis Area and Severity Index ≥90% improvement (PASI 90), 62.9% vs. 3.8%; static Physician Global Assessment (sPGA) 0/1, 78.1% vs. 9.6%; both p< .001) in study 1; in study 2, PASI 90 and sPGA 0/1 were 66.7%, and 81.5%, respectively. All patients successfully self-administered study treatments via PFS or AI. Acceptability of self-injection was high in both studies. Efficacy and safety of risankizumab 150 mg/mL were comparable with results from previous risankizumab phase 3 studies using the 90 mg/mL formulation. Conclusions The efficacy, safety, and usability of 150 mg/mL risankizumab delivered as a single PFS or AI injection support use of this new formulation in patients with moderate to severe plaque psoriasis. Clinical trials NCT03875482 and NCT038750

    Adalimumab Effectiveness Up to Six Years in Adalimumab-naïve Patients with Crohn's Disease: Results of the PYRAMID Registry

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    BACKGROUND: PYRAMID was an international multicenter, noninterventional, postmarketing registry assessing long-term safety and effectiveness of adalimumab (Humira), as used in routine clinical practice. METHODS: Adult patients with moderately to severely active Crohn's disease with or without prior adalimumab experience were enrolled in the registry and followed for up to 6 years. Effectiveness measurements included the Physician's Global Assessment (PGA, a composite of Harvey Bradshaw Index [HBI] and rectal bleeding score), clinical remission (HBI < 5), Short Inflammatory Bowel Disease Questionnaire (SIBDQ), and Work Productivity and Activity Impairment (WPAI) questionnaire. Data were reported for adalimumab-naïve patients and analyzed by baseline immunomodulator use and disease duration. RESULTS: This study evaluated 2057 adalimumab-naïve patients. Mean PGA improved from 7.5 (baseline) to 3.9 (year 1) and 3.3 (year 6). The proportion of patients in HBI remission increased from 29% (573 of 1969; baseline) to 68% (900 of 1331; year 1) and 75% (625 of 831; year 6). Patients stratified by baseline immunomodulator use had similar HBI remission rates; patients with disease duration <2 years achieved numerically higher HBI remission rates than patients with longer disease duration. Patient-reported SIBDQ and WPAI scores improved at year 1; all WPAI subscore improvements were clinically meaningful (≥7% point change) at year 1 and maintained through year 6. Serious infections were reported in 11.1% of patients; incidence rates of malignancies, lymphoma, and demyelinating disorders were low. CONCLUSION: Adalimumab therapy, as used in routine clinical practice, improved physician-reported and patient-reported disease outcomes and remission rates for up to 6 years. No new safety signals were observed

    Efficacy and safety of risankizumab for active psoriatic arthritis : 24-week results from the randomised, double-blind, phase 3 KEEPsAKE 2 trial

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    Objectives Risankizumab is an interleukin-23 inhibitor under study for the treatment of patients with psoriatic arthritis (PsA). The phase 3 KEEPsAKE 2 trial investigated the efficacy and safety of risankizumab versus placebo in patients with active PsA who had previous inadequate response or intolerance to = 1 conventional synthetic disease-modifying antirheumatic drug (csDMARD-IR). Results through week 24 are reported here. Methods Adults with PsA who were Bio-IR and/or csDMARD-IR were randomised to receive subcutaneously administered risankizumab 150 mg or placebo at weeks 0, 4 and 16 during a 24-week, double-blind treatment period. The primary endpoint was the proportion of patients who achieved >= 20% improvement in American College of Rheumatology score (ACR20) at week 24. Secondary endpoints assessed key domains of PsA and patient-reported outcomes. Results A total of 444 patients (median age 53 years, range 23-84 years) were randomised to risankizumab (n=224) or placebo (n=220); 206 patients (46.5%) were Bio-IR. At week 24, a significantly greater proportion of patients receiving risankizumab achieved the primary endpoint of ACR20 (51.3% vs 26.5%, p<0.001) and all secondary endpoints (p<0.05) compared with placebo. Serious adverse events were reported for 4.0% and 5.5% of risankizumab-treated and placebo-treated patients, respectively; serious infections were reported for 0.9% and 2.3%, respectively. Conclusion Treatment with risankizumab resulted in significant improvements versus placebo in key disease outcomes and was well tolerated in patients with PsA who were Bio-IR and/or csDMARD-IR.arthritis; arthritis; psoriatic; biological therap

    Lymphoma Risk and Overall Safety Profile of Adalimumab in Patients With Crohn's Disease With up to 6 Years of Follow-Up in the Pyramid Registry

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    Objectives: Real-world, prospective, long-term studies in Crohn's disease (CD) characterizing adalimumab safety data and lymphoma risk were lacking. We present the final results from the PYRAMID registry, which was designed to rule out a doubling of lymphoma risk in adalimumab-treated patients with CD. Methods: Patients with moderately to severely active CD newly prescribed or currently receiving adalimumab according to local product labels were followed for up to 6 years and analyzed for adverse events (AEs). The registry exposure-adjusted observed rate of lymphoma was compared with the estimated background lymphoma rate from a sex-matched general population in the Surveillance, Epidemiology, and End Results 17 Registry database adjusted for anticipated prior or concurrent thiopurine use in a CD population. Results: A total of 5025 patients were evaluated (16680.4 PY of adalimumab registry exposure, ≈3 years/patient mean follow-up). Registry treatment-emergent AEs included 4129 serious AEs (n = 1853 [36.9%]; 24.8 E/100 PY), 792 serious infections (n = 556 [11.1%]; 4.7 E/100 PY), and 134 malignancies (n = 116 [2.3%]; 0.8 E/100 PY), including ten lymphomas. The observed lymphoma rate (0.060 E/100 PY) was lower than the estimated background rate (0.084 E/100 PY), and the upper bound of the one-sided 95% CI of the observed rate (0.102 E/100 PY) was lower than double the estimated rate (0.168 E/100 PY). Conclusions: PYRAMID is the longest prospective adalimumab study in routine clinical practice, with up to 6 years of follow-up. No new safety signals were reported. The pre-specified registry objective of ruling out a doubling of lymphoma risk with adalimumab was met

    Regression of advanced diabetic nephropathy by hepatocyte growth factor gene therapy in rats

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    Diabetic nephropathy is the main cause of end-stage renal disease requiring dialysis in developed countries. In this study, we demonstrated the therapeutic effect of hepatocyte growth factor (HGF) on advanced rather than early diabetic nephropathy using a rat model of streptozotocin-induced diabetes. Early diabetic nephropathy (16 weeks after induction of diabetes) was characterized by albuminuria, hyperfiltration, and glomerular hypertrophy, whereas advanced diabetic nephropathy showed prominent transforming growth factor (TGF)-beta1 upregulation, mesangial expansion, and glomerulosclerosis. An SP1017-formulated human HGF (hHGF) plasmid was administered by intramuscular injection combined with electroporation over a 30-day follow-up in rats with early and advanced diabetic nephropathy. hHGF gene therapy upregulated endogenous rat HGF in the diabetic kidney (rat HGF by RT-PCR was threefold higher than in diabetic rats without therapy). hHGF gene therapy did not improve functional or morphologic abnormalities in early diabetic nephropathy. hHGF gene therapy reduced albuminuria and induced strong regression of mesangial expansion and glomerulosclerosis in advanced diabetic nephropathy. These findings were associated with suppression of renal TGF-beta1 and mesangial connective tissue growth factor (CTGF) upregulation, inhibition of renal tissue inhibitor of metalloproteinase (TIMP)-1 expression, and reduction of renal interstitial myofibroblasts. In conclusion, our results suggest that hHGF gene therapy may be considered as an innovative therapeutic strategy to treat advanced diabetic nephropathy
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