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PURPOSE: To demonstrate the safety and feasibility of the Urocross Expander System (formerly branded as XFLO Expander System), an implantable nitinol tissue expander to trea t patients with lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: Men of 50 years or older were eligible to participate in the international, prospective, three-arm, open-label EXPANDER-1 trial if they had a prostate volume between 30 and 80 cc, prostatic urethra length between 20 and 60/80 mm, international prostate symptom score (IPSS) > 13, peak urinary flow (Qmax) < 12 mL/s, post-void residual (PVR) urine volume < 250 mL and quality of life (QoL) score ≥ 3. Patients had pre-assigned implant indwell times (1, 6, and 12 months for Arm-1, Arm-2 and Arm-3 respectively) with follow-up through 6 months (Arm-1) and 3 years (Arm-2 and Arm-3) post-retrieval. RESULTS: Outcome from treated subjects with their 6-month post-retrieval will be presented in this manuscript, as data collection from longer-term follow-up is ongoing. As of May 24, 2021, 39 and 22 men (mean age: 65), respectively, had implants successfully deployed and retrieved without any complications. No cases of implant encrustation were observed. Device- and procedure-related adverse events were predominantly mild to moderate in severity. Three SAEs were reported. Only one patient required catheterization post-implant for more than three days. Improvements in clinical parameters such as IPSS, QoL, PVR and Qmax as well as sexual function were observed. CONCLUSIONS: Preliminary results demonstrate that the Urocross Expander System is a feasible and safe procedure for treating BPH/LUTS. A strong signal of efficacy justifies further evaluation of this PRostatic Urethral Expansion (PURE) procedure. Negative features of earlier generations of prostatic implants such as biocompatibility, migrations and encrustation have possibly been overcome.
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Síntomas del Sistema Urinario Inferior , Hiperplasia Prostática , Neoplasias de la Próstata , Anciano , Humanos , Síntomas del Sistema Urinario Inferior/etiología , Síntomas del Sistema Urinario Inferior/cirugía , Masculino , Estudios Prospectivos , Hiperplasia Prostática/complicaciones , Hiperplasia Prostática/cirugía , Neoplasias de la Próstata/complicaciones , Calidad de Vida , Dispositivos de Expansión Tisular/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Urinary tract infections (UTIs) are among the most prevalent microbial diseases and their financial burden on society is substantial. In the context of increasing antibiotic resistance, finding alternative treatments for UTIs is a top priority. We aimed to determine whether intravesical bacteriophage therapy with a commercial bacteriophage cocktail is effective in treating UTI. METHODS: We did a randomised, placebo-controlled, clinical trial, at the Alexander Tsulukidze National Centre of Urology, Tbilisi, Georgia. Men older than 18 years of age, who were scheduled for transurethral resection of the prostate (TURP), with complicated UTI or recurrent uncomplicated UTI but no signs of systemic infection, were allocated by block randomisation in a 1:1:1 ratio to receive intravesical Pyo bacteriophage (Pyophage; 20 mL) or intravesical placebo solution (20 mL) in a double-blind manner twice daily for 7 days, or systemically applied antibiotics (according to sensitivities) as an open-label standard-of-care comparator. Urine culture was taken via urinary catheter at the end of treatment (ie, day 7) or at withdrawal from the trial. The primary outcome was microbiological treatment response after 7 days of treatment, measured by urine culture; secondary outcomes included clinical and safety parameters during the treatment period. Analyses were done in a modified intention-to-treat population of patients having received at least one dose of the allocated treatment regimen. This trial is registered with ClinicalTrials.gov, NCT03140085. FINDINGS: Between June 2, 2017, and Dec 14, 2018, 474 patients were screened for eligibility and 113 (24%) patients were randomly assigned to treatment (37 to Pyophage, 38 to placebo, and 38 to antibiotic treatment). 97 patients (28 Pyophage, 32 placebo, 37 antibiotics) received at least one dose of their allocated treatment and were included in the primary analysis. Treatment success rates did not differ between groups. Normalisation of urine culture was achieved in five (18%) of 28 patients in the Pyophage group compared with nine (28%) of 32 patients in the placebo group (odds ratio [OR] 1·60 [95% CI 0·45-5·71]; p=0·47) and 13 (35%) of 37 patients in the antibiotic group (2·66 [0·79-8·82]; p=0·11). Adverse events occurred in six (21%) of 28 patients in the Pyophage group compared with 13 (41%) of 32 patients in the placebo group (OR 0·36 [95% CI 0·11-1·17]; p=0·089) and 11 (30%) of 37 patients in the antibiotic group (0·66 [0·21-2·07]; p=0·47). INTERPRETATION: Intravesical bacteriophage therapy was non-inferior to standard-of-care antibiotic treatment, but was not superior to placebo bladder irrigation, in terms of efficacy or safety in treating UTIs in patients undergoing TURP. Moreover, the bacteriophage safety profile seems to be favourable. Although bacteriophages are not yet a recognised or approved treatment option for UTIs, this trial provides new insight to optimise the design of further large-scale clinical studies to define the role of bacteriophages in UTI treatment. FUNDING: Swiss Continence Foundation, the Swiss National Science Foundation, and the Swiss Agency for Development and Cooperation. TRANSLATIONS: For the Georgian and German translations of the abstract see Supplementary Materials section.
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Bacteriófagos/crecimiento & desarrollo , Terapia de Fagos/métodos , Resección Transuretral de la Próstata/efectos adversos , Infecciones Urinarias/terapia , Anciano , Antibacterianos/uso terapéutico , Método Doble Ciego , Georgia , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/etiologíaRESUMEN
Urinary tract infections (UTIs) are among the most widespread microbial diseases and their economic impact on the society is substantial. The continuing increase of antibiotic resistance worldwide is worrying. As a consequence, well-tolerated, highly effective therapeutic alternatives are without delay needed. Although it has been demonstrated that bacteriophage therapy may be effective and safe for treating UTIs, the number of studied patients is low and there is a lack of randomized controlled trials (RCTs). The present study has been designed as a two-phase prospective investigation: (1) bacteriophage adaptation, (2) treatment with the commercially available but adapted Pyo bacteriophage. The aim was to evaluate feasibility, tolerability, safety, and clinical/microbiological outcomes in a case series as a pilot for a double-blind RCT. In the first phase, patients planned for transurethral resection of the prostate were screened (n = 130) for UTIs and enrolled (n = 118) in the study when the titer of predefined uropathogens (Staphylococcus aureus, E. coli, Streptococcus spp., Pseudomonas aeruginosa, Proteus mirabilis) in the urine culture was ≥104 colony forming units/mL. In vitro analysis showed a sensitivity for uropathogenic bacteria to Pyo bacteriophage of 41% (48/118) and adaptation cycles of Pyo bacteriophage enhanced its sensitivity to 75% (88/118). In the second phase, nine patients were treated with adapted Pyo bacteriophage and bacteria titer decreased (between 1 and 5 log) in six of the nine patients (67%). No bacteriophage-associated adverse events have been detected. The findings of our prospective two-phase study suggest that adapted bacteriophage therapy might be effective and safe for treating UTIs. Thus, well-designed RCTs are highly warranted to further define the role of this potentially revolutionizing treatment option.
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BACKGROUND: Urinary tract infections (UTI) are among the most prevalent microbial diseases and their financial burden on society is substantial. The continuing increase of antibiotic resistance worldwide is alarming. Thus, well-tolerated, highly effective therapeutic alternatives are urgently needed. Although there is evidence indicating that bacteriophage therapy may be effective and safe for treating UTIs, the number of investigated patients is low and there is a lack of randomized controlled trials. METHODS AND DESIGN: This study is the first randomized, placebo-controlled, double-blind trial investigating bacteriophages in UTI treatment. Patients planned for transurethral resection of the prostate are screened for UTIs and enrolled if in urine culture eligible microorganisms ≥104 colony forming units/mL are found. Patients are randomized in a double-blind fashion to the 3 study treatment arms in a 1:1:1 ratio to receive either: a) bacteriophage (i.e. commercially available Pyo bacteriophage) solution, b) placebo solution, or c) antibiotic treatment according to the antibiotic sensitivity pattern. All treatments are intended for 7 days. No antibiotic prophylaxes will be given to the double-blinded treatment arms a) and b). As common practice, the Pyo bacteriophage cocktail is subjected to periodic adaptation cycles during the study. Urinalysis, urine culture, bladder and pain diary, and IPSS questionnaire will be completed prior to and at the end of treatment (i.e. after 7 days) or at withdrawal/drop out from the study. Patients with persistent UTIs will undergo antibiotic treatment according to antibiotic sensitivity pattern. DISCUSSION: Based on the high lytic activity and the potential of resistance optimization by direct adaptation of bacteriophages, and considering the continuing increase of antibiotic resistance worldwide, bacteriophage therapy is a very promising treatment option for UTIs. Thus, our randomized controlled trial investigating bacteriophages for treating UTIs will provide essential insights into this potentially revolutionizing treatment option. TRIAL REGISTRATION: This study has been registered at clinicaltrials.gov ( www.clinicaltrials.gov/ct2/show/NCT03140085 ). April 27, 2017.
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Bacteriófagos , Terapia de Fagos/métodos , Resección Transuretral de la Próstata/efectos adversos , Infecciones Urinarias/terapia , Bacteriófagos/crecimiento & desarrollo , Método Doble Ciego , Humanos , Masculino , Resultado del Tratamiento , Infecciones Urinarias/diagnóstico , Infecciones Urinarias/etiologíaRESUMEN
BACKGROUND: Urinary tract infections (UTIs) are among the most prevalent microbial diseases and their financial burden on society is substantial. The continuing increase of antibiotic resistance worldwide is alarming so that well-tolerated, highly effective therapeutic alternatives are urgently needed. OBJECTIVE: To investigate the effect of bacteriophages on Escherichia coli and Klebsiella pneumoniae strains isolated from the urine of patients suffering from UTIs. MATERIAL AND METHODS: Forty-one E. coli and 9 K. pneumoniae strains, isolated from the urine of patients suffering from UTIs, were tested in vitro for their susceptibility toward bacteriophages. The bacteriophages originated from either commercially available bacteriophage cocktails registered in Georgia or from the bacteriophage collection of the George Eliava Institute of Bacteriophage, Microbiology and Virology. In vitro screening of bacterial strains was performed by use of the spot-test method. The experiments were implemented three times by different groups of scientists. RESULTS: The lytic activity of the commercial bacteriophage cocktails on the 41 E. coli strains varied between 66% (Pyo bacteriophage) and 93% (Enko bacteriophage). After bacteriophage adaptation of the Pyo bacteriophage cocktail, its lytic activity was increased from 66 to 93% and only one E. coli strain remained resistant. One bacteriophage of the Eliava collection could lyse all 9 K. pneumoniae strains. CONCLUSIONS: Based on the high lytic activity and the potential of resistance optimization by direct adaption of bacteriophages as reported in this study, and in view of the continuing increase of antibiotic resistance worldwide, bacteriophage therapy is a promising treatment option for UTIs highly warranting randomized controlled trials.
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The goal of the study was to evaluate expression of the cell-cycle regulatory proteins (p27(Kip1) and cyclin D3) and proliferation marker Ki67 in normal human kidneys and renal cell carcinoma (RCC) tissues. Intensity of the markers' expression was prospectively studied and compared between normal and RCC tissue samples. Association was analyzed with cancer clinical parameters. p27(Kip1) was significantly upregulated in normal compared with in RCC samples. Immunoreactivity of the protein negatively correlated with tumor size and was associated with pathological stage and grade. Patients with symptomatic disease had significantly less marker expression than those with incidentally discovered tumors. Intensity of Ki67 staining positively correlated with primary tumor size and associated with disease stage and grade. Cyclin D3 immunoreactivity positively correlated with tumor size. Loss of p27(Kip1) expression, pathological stage, grade, and tumor size were risk factors for disease recurrence (P = 0.0072, 0.0011, and 0.0467, and P < 0.0001, respectively) and patient death (P = 0.0021, 0.0106, 0.0151, and 0.0021, respectively). With Cox multivariate analysis loss of p27(Kip1) expression (hazard ratio 9.3, P = 0.002) and tumor size (hazard ratio 5.9, P = 0.015) were the predictors of cancer-specific survival. In conclusion, intensity of the markers' expression in RCC is associated with tumour clinical parameters (size, stage, grade, and disease presentation type). Loss of p27(Kip1) expression is a risk factor for the disease recurrence and cancer-related patient death.
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Carcinoma de Células Renales/metabolismo , Neoplasias Renales/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Estudios de Casos y Controles , Ciclina D3 , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Ciclinas/metabolismo , Supervivencia sin Enfermedad , Femenino , Humanos , Antígeno Ki-67/metabolismo , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Adulto JovenRESUMEN
p27((Kip1)), cyclin D3 and Ki67 are the markers of DNA damage and cell proliferation. The goal of the current study was to analyze expression of the markers in benign and malignant prostate cancer tissues. Activity of p27((Kip1)), cyclin D3 and Ki67 was immunohistochemically evaluated in different cells of BPH, prostate cancer (PCa) and hormonally treated prostate cancer (HTPCa) tissues. The tissue samples were derived by means of TURP or radical prostatectomy. Intensity of the expression was compared between the groups, and association was sought with clinical parameters. Total expression of p27((Kip1)) was significantly higher in BPH as compared with PCa. Epithelial marker expression was higher in HTPCa than in PCa. Intensity of the expression in epithelial, vascular and ductal cells was negatively associated with the tumor stage and Gleason grades. Total Ki67 activity was positively correlated with patient age and serum PSA level. There was significantly higher expression in PCa and hormone-escaped PCa (HEPCa) as compared with BPH. Epithelial and vascular marker expression was positively associated with tumor stage and Gleason grades. There was a positive correlation between cyclin D3 and serum PSA level. With the increase of Gleason grades, cyclin D3 expression increased significantly. Expression of p27((Kip1)) negatively correlated with Ki67 and cyclin D3, while the latter two markers correlated positively. p27((Kip1)) is down-regulated, whereas Ki67 and cyclin D3 are up-regulated in PCa. Intensity of the markers' expression is associated with tumor stage and grades. Hormonotherapy of PCa causes activation of p27((Kip1)). HEPCa is characterized by increased Ki67 expression.
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Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Ciclinas/metabolismo , Antígeno Ki-67/metabolismo , Hiperplasia Prostática/metabolismo , Neoplasias de la Próstata/metabolismo , Anciano , Análisis de Varianza , Biomarcadores de Tumor/metabolismo , Ciclina D3 , Daño del ADN , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/tratamiento farmacológico , Estadísticas no Paramétricas , Células Tumorales Cultivadas/efectos de los fármacos , Células Tumorales Cultivadas/metabolismoRESUMEN
The importance of cyclin-dependent kinase inhibitors (CDKI) in benign and malignant urological diseases is a subject of intense ongoing investigation. The goal of the current study was to analyze the expression of p27((Kip1))CDKI in benign and malignant renal cells and assess their possible association with different clinical parameters. Expression of p27((Kip1)) was evaluated and compared in 24 normal human kidneys and in 52 renal cell carcinoma (RCC) tissue samples. Intensity of the expression was compared between the groups and association was analyzed with cancer clinical parameters. The expression of the marker was significantly higher in normal than in RCC samples (P = 0.0045). Intensity of p27((Kip1)) expression in RCC was negatively correlated with tumor size (Rho = -0.438, P = 0.0051) and associated with pathological stage and grade (P = 0.0488 and < 0.0001, respectively). The patients with symptomatic disease had significantly less marker expression than incidentally discovered tumors (P = 0.0301). Loss of p27((Kip1)) expression, pathological stage, grade and tumor size were the risk-factors for disease recurrence (P = 0.0072, 0.0011, 0.0467 and < 0.0001, respectively) and patient survival (P = 0.0021, 0.0106, 0.0151 and 0.0021, respectively). With Cox multivariate analysis loss of p27((Kip1)) expression (hazard ratio 9.3, P = 0.002) and tumor size (hazard ratio 5.9, P = 0.015) were the predictors of cancer-specific survival. Expression of p27((Kip1)) is significantly decreased in RCC as compared with normal kidney tissue. Intensity of the expression is associated with clinical parameters: tumor size, stage, grade and disease presentation. Loss of p27((Kip1)) expression is a risk-factor for disease recurrence and the strongest predictor of cancer-specific survival.
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Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias Renales/genética , Recurrencia Local de Neoplasia/genética , Adulto , Anciano , Anciano de 80 o más Años , Inhibidor p27 de las Quinasas Dependientes de la Ciclina , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
The aim of this study was to evaluate the influence of renal ischemia, cold preservation and reperfusion on the degree of renal kidney senescence. An experimental model of ex vivo renal hemoperfusion was used. Expression of p16(INK4a), p21(WAF1/CIP1) and p27(Kip1) cyclin-dependent kinase inhibitor genes (CDKIGs) was studied immunohistochemically in kidney biopsy samples at baseline and different time points after reperfusion. All three markers were up-regulated in kidney tissue after the reperfusion; however, their activation in different renal cells varied according to the reperfusion time. Expression of p16 was significantly increased in tubular cells at 180 min of reperfusion when compared with the baseline. Activation of p27 was detected in glomerular cells at 15 min and was significantly higher at 60, 120 and 180 min of reperfusion. The marker started increasing in tubular cells at 15 min and was elevated at every time point afterwards. p21 was significantly over-expressed in all renal cells after the reperfusion. It has been shown by the results of the current study that renal ischemia/reperfusion is associated with over-expression of CDKIGs indicating on substantial DNA damage and/or accelerated tissue senescence. For the first time it has been shown that tissue expression of CDKIGs is positively related with the reperfusion time.
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Ciclo Celular/genética , Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/antagonistas & inhibidores , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/antagonistas & inhibidores , Riñón/irrigación sanguínea , Animales , Isquemia , Reperfusión , PorcinosRESUMEN
The telomere (T) length, p21(WAF1/CIP1) and p27(Kip1) cyclin-dependent kinase inhibitor (CDKI) genes are the markers of cell senescence and DNA damage. The aim of the study was to determine the influence of renal ischaemia/reperfusion (I/R) and anti-lymphocyte function-associated antigen-1 (LFA-1) monoclonal antibody (mAb) treatment on the value of the above-mentioned markers. Significantly higher levels of p21 and p27 were expressed by the glomeruli (P=0.001 and P=0.0001), tubules (P=0.0065 and P=0.0006), and interstitial cells (P=0.0017 and P=0.0022, respectively) of the xenoperfused kidneys. The mean T length of non-perfused renal specimens (5.56+/-0.60 kbp) was longer than that of the xenoperfused kidneys (5.46+/-0.36 kbp) [P= non-significant (NS)]. Addition of anti-LFA-1 mAb did not significantly influence the gene expression profile in the xenoperfused kidneys. The mean T length was longer in the kidneys with anti-LFA-1 mAb than in those without the medication (5.7+/-0.11 vs 5.13+/-0.31 kbp) (P=0.0661). Kidney I/R is associated with telomere shortening and an over-expression of p21 and p27 CDKIs, which indicates substantial DNA damage and/or accelerated tissue senescence. Although anti-LFA-1 mAb had some protective effect on the telomeres, it did not influence the gene expression profile in this study.
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Proteínas de Ciclo Celular/metabolismo , Hemoperfusión , Riñón/irrigación sanguínea , Antígeno-1 Asociado a Función de Linfocito/metabolismo , Daño por Reperfusión/genética , Daño por Reperfusión/patología , Telómero/genética , Animales , Anticuerpos Monoclonales/inmunología , Proteínas de Ciclo Celular/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Inhibidor p27 de las Quinasas Dependientes de la Ciclina , Expresión Génica , Humanos , Inmunohistoquímica , Riñón/metabolismo , Antígeno-1 Asociado a Función de Linfocito/inmunología , Macaca fascicularis , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
OBJECTIVES: Living-unrelated donors may become an additional organ source for patients on the kidney waiting list. We studied the impact of a combination of calcineurin inhibitors and mycophenolate-mofetil together with steroids on the outcomes of living-related (LRD), unrelated (LUR), and cadaver transplantation. METHODS: Between September 1997 and January 2000, 129 patients underwent LRD (n = 80) or LUR (n = 49) kidney transplantation, and another 173 patients received a cadaveric kidney. Immunosuppressive protocols consisted of mycophenolate-mofetil with cyclosporine-Neoral (41%) or tacrolimus (59%) plus steroids. We compared the patient and graft survival data, rejection rate, and graft functional parameters. RESULTS: LRD recipients were younger (33.6 years) than LUR (47.8 years) and cadaver (43.7 years) donor recipients (P <0.001). HLA matching was higher in LRD patients (P <0.001). Acute rejection developed in 28.6% of LUR versus 27.5% of LRD transplants and 29.7% of cadaver kidney recipients (P = not significant). The creatinine level at 1, 2, and 3 years after transplant was 1.63, 1.73, and 1.70 mg% for LRD patients; 1.48, 1.48, and 1.32 mg% for LUR patients; and 1.75, 1.68, and 1.67 mg% for cadaver kidney recipients (P = not significant), respectively. No difference in patient survival rates was found among the groups. The 1, 2, and 3-year graft survival rates were significantly better in recipients of LRD (91.3%, 90.0%, and 87.5%, respectively) and LUR transplants (89.8%, 87.8%, and 87.8%, respectively) than in cadaver kidney recipients (81.5%, 78.6%, 76.3%, respectively; P <0.01). CONCLUSIONS: Despite HLA disparity, the rejection and survival rates of LUR transplants under current immunosuppressive protocols are comparable to those of LRD and better than those of cadaveric transplants.
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Inmunosupresores/uso terapéutico , Trasplante de Riñón/estadística & datos numéricos , Donadores Vivos , Ácido Micofenólico/análogos & derivados , Adulto , Suero Antilinfocítico/administración & dosificación , Suero Antilinfocítico/uso terapéutico , Cadáver , Inhibidores de la Calcineurina , Ciclosporina/administración & dosificación , Ciclosporina/uso terapéutico , Femenino , Rechazo de Injerto/epidemiología , Supervivencia de Injerto , Humanos , Inmunosupresores/administración & dosificación , Masculino , Metilprednisolona/administración & dosificación , Metilprednisolona/uso terapéutico , Persona de Mediana Edad , Muromonab-CD3/administración & dosificación , Muromonab-CD3/uso terapéutico , Ácido Micofenólico/administración & dosificación , Ácido Micofenólico/uso terapéutico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Análisis de Supervivencia , Tacrolimus/administración & dosificación , Tacrolimus/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Recent advances in immunosuppressive therapy have led to a substantial improvement in the outcome of kidney transplantation. Living unrelated donors may become a source of additional organs for patients on the kidney waiting list. OBJECTIVES: To study the impact of the combination of calcineurin inhibitors and mycophenolate-mofetile, together with steroids, on outcomes of living related and unrelated transplants. METHODS: Between September 1997 and January 2000, 129 patients underwent living related (n = 80) or unrelated (n = 49) kidney transplant. The mean follow-up was 28.2 months. Immunosuppressive protocols consisted of MMF with cyclosporine (41%) or tacrolimus (59%), plus steroids. Patient and graft survival data, rejection rate, and graft functional parameters were compared between the groups. RESULTS: LUD recipients were older (47.8 vs. 33.6 years) with a higher number of re-transplants (24.5% vs. 11.2% in LRD recipients, P < 0.05). Human leukocyte antigen matching was higher in LRD recipients (P < 0.001). Acute rejection developed in 28.6% of LUD and 27.5% of LRD transplants (P = NS). Creatinine levels at 1, 2 and 3 years post-transplant were 1.6, 1.7 and 1.7 mg/dl for LRD patients and 1.5, 1.5 and 1.3 mg/dl for LUD recipients (P = NS). There was no difference in patient survival rates between the groups. One, 2 and 3 years graft survival rates were similar in LRD (91.3%, 90% and 87.5%) and LUD (89.8%, 87.8% and 87.8%) recipients. CONCLUSIONS: Despite HLA disparity, rejection and survival rates of living unrelated transplants under current immunosuppressive protocols are comparable to those of living related transplants.
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Terapia de Inmunosupresión/estadística & datos numéricos , Trasplante de Riñón/estadística & datos numéricos , Donadores Vivos/estadística & datos numéricos , Obtención de Tejidos y Órganos/métodos , Obtención de Tejidos y Órganos/estadística & datos numéricos , Adulto , Distribución por Edad , Creatinina/sangre , Diabetes Mellitus/epidemiología , Donación Directa de Tejido/estadística & datos numéricos , Femenino , Rechazo de Injerto/epidemiología , Humanos , Incidencia , Israel/epidemiología , Masculino , Persona de Mediana Edad , Evaluación de Procesos y Resultados en Atención de Salud , Diálisis Renal/estadística & datos numéricos , Reoperación/estadística & datos numéricos , Análisis de SupervivenciaRESUMEN
BACKGROUND: The goal of the current study was to examine the potential value of p16(INK4a) and p27(Kip1) cyclin-dependent kinase inhibitor (CDKI) genes in the process of human kidney aging in vivo, and in the development of chronic allograft nephropathy (CAN). METHODS: Expression of p16(INK4a) and p27(Kip1) CDKI genes was evaluated and compared in 20 normal human kidney tissues of different ages (range, 21 to 80 years) and in 9 chronically rejected kidney grafts. Age dependency of marker expression was analyzed by the Pearson correlation and linear regression. RESULTS: Expression of p16 in cortical tubular (CTS) and interstitial (CIS) cells of normal kidney was age dependent (correlation coefficients: 0.608 and 0.726, 95% confidence interval [CI]: 0.227 to 0.828 and 0.417 to 0.884, respectively). Cortical tubular expression of p27 was also correlated with increasing age (0.672, 95% CI: 0.327 to 0.859). Linear regression analyses confirmed the linearity of marker relationship with age (coefficient of determination R(2):0.370, 0.452, and 0.527 for CIS p16, CTS p27, and CTS p16, respectively). The mean chronological and predicted graft ages (53 +/- 21 and 76 +/- 8.9 years, respectively) were significantly different (P = 0.0126). The glomeruli, tubules, and interstitial cells of rejected grafts expressed significantly higher levels of p16 and p27 than normal kidneys. Expression of p16 in glomerular and cortical interstitial cells was higher in grade 3 of CAN than in grade 2 (P = 0.013 and 0.004, respectively). CONCLUSION: The results of the current study show that expression of p16(INK4a) and p27(Kip1) CDKI genes is increased in cortical cells of the aging human kidney and in chronic allograft rejection, supporting the senescence theory of CAN.
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Envejecimiento/metabolismo , Proteínas de Ciclo Celular/biosíntesis , Inhibidor p16 de la Quinasa Dependiente de Ciclina/biosíntesis , Regulación de la Expresión Génica , Genes p16 , Rechazo de Injerto/metabolismo , Enfermedades Renales/metabolismo , Trasplante de Riñón , Proteínas Supresoras de Tumor/biosíntesis , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/genética , Proteínas de Ciclo Celular/genética , Enfermedad Crónica , Inhibidor p27 de las Quinasas Dependientes de la Ciclina , Femenino , Glomerulonefritis/cirugía , Rechazo de Injerto/genética , Humanos , Corteza Renal/metabolismo , Corteza Renal/patología , Enfermedades Renales/etiología , Enfermedades Renales/genética , Masculino , Persona de Mediana Edad , Nefroesclerosis/cirugía , Trasplante Homólogo , Proteínas Supresoras de Tumor/genéticaRESUMEN
The p21 (WAF1/CIP1) cyclin-dependent kinase (CDK) inhibitor gene is considered to be the senescence marker in some recent publications. Expression of the gene was evaluated in 14 normal human kidney tissues of different ages and in nine chronically rejected renal allografts. All normal kidneys were negative for p21 expression. Glomerular, tubular and interstitial expression of the marker was detected in 88.9% ( P<0.0001) and vascular expression in 66.7% of chronically rejected grafts ( P<0.001). No correlation was found between the intensity of p21 expression and recipient age, donor age or number of human leukocyte antigen (HLA) mismatches. The marker was expressed more in grade 3 of chronic allograft nephropathy (CAN) than in grade 2 ( P=0.059 for glomerular score). Tubular expression of p21 was correlated with the number of acute rejections: P<0.05 for three vs one and two, and P=0.0046 for three vs no previous acute rejection episodes.
Asunto(s)
Ciclinas/metabolismo , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/metabolismo , Trasplante de Riñón , Riñón/metabolismo , Enfermedad Aguda , Adulto , Biomarcadores , Enfermedad Crónica , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trasplante Homólogo , Regulación hacia ArribaRESUMEN
OBJECTIVES: The telomere (T) length, p21(WAF1/CIP1) and p27(Kip1) cyclin dependent kinase inhibitor (CDKI) genes are considered the markers of cell senescence and DNA damage. The aim of the study was to evaluate the influence of renal ischemia/reperfusion (I/R) on the value of above-mentioned markers. METHODS: 13 Macaque cynomolgus monkey kidneys were harvested and placed in Eurocollins solution. 9 kidneys were ex-vivo perfused with human blood and 4 kidneys were not perfused at all (control group). Tissue expression of p21(WAF1/CIP1) and p27(Kip1) was evaluated immunohistochemically and the T lengths were measured by southern blotting technique. RESULTS: Significantly higher levels of p21 and p27 were expressed by the glomeruli (p = 0.001 and 0.0001), tubules (p = 0.0065 and 0.0006) and interstitial cells (p = 0.0017 and 0.0022, respectively) of the xenoperfused kidneys. The mean T length was higher in the control group (5.56 +/- 0.60 kbp) than in the study group kidneys (5.46 +/- 0.36 kbp) (P = NS). CONCLUSION: Renal I/R is associated with telomere shortening and an over-expression of p21 and p27 genes indicating substantial DNA damage and/or accelerated tissue senescence.