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1.
Transplantation ; 2019 Nov 20.
Artículo en Inglés | MEDLINE | ID: mdl-31815900

RESUMEN

BACKGROUND: Better preservation strategies for the storage of DCD grafts are essential to improve graft function and to increase the kidney donor pool. We compared continuous Normothermic Ex Vivo Kidney Perfusion (NEVKP) with hypothermic anoxic machine perfusion (HAMP) and static cold storage (SCS) in a porcine kidney autotransplantation model. METHODS: Porcine kidneys were exposed to 30min of warm ischemia and then reimplanted following either 16hr of either SCS, HAMP (LifePort 1.0) or NEVKP prior to autotransplantation (n=5 per group). The contralateral kidney was removed. Animals were followed for 8 days. RESULTS: Grafts preserved by NEVKP demonstrated improved function with more rapid recovery compared to HAMP and SCS (mean peak serum creatinine: 3.66+/-1.33mg/dl (postoperative day 1; POD1), 8.82+/-3.17mg/dl (POD2), and 12.90+/-2.19mg/dl (POD3), respectively). The NEVKP group demonstrated significantly increased creatinine clearance calculated on POD3 (63.6+/-19.0ml/min) compared to HAMP (13.5+/-10.3ml/min, p=0.001) and SCS (4.0+/-2.6ml/min,p=0.001). Histopathologic injury scores on POD8 were lower in both perfused groups (NEVKP and HAMP, score: 1-1.5) compared to SCS (score: 1-3, p=0.3), without reaching statistical significance. CONCLUSIONS: NEVKP storage significantly improved early kidney function compared to both cold preservation strategies, although HAMP also demonstrates improvement over SCS. NEVKP may represent a novel, superior preservation option for DCD renal grafts compared to conventional hypothermic methods.

2.
Exp Clin Transplant ; 2019 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-31615379

RESUMEN

Lung transplant recipients are at risk of developing many kinds of lung infection, such as community-acquired, nosocomial, opportunistic, and endemic. Here, we report a young lung transplant recipient who developed blastomycosis, which had most likely occurred following eculizumab treatment for atypical hemolytic uremia syndrome. We hypothesize that the agent interfering with C5 would influence the immune response against Blastomyces species.Although eculizumab has opened a new era for treatment of atypical hemolytic uremia syndrome and has led to the understanding that complementmediated pathology is needed, the risk of potentially fatal infections by blocking the complement pathway has not been fully elucidated. Careful follow-up and frequent tests to look for infections are needed after using this monoclonal antibody.

3.
Transplantation ; 103(6): e146-e158, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30801542

RESUMEN

BACKGROUND: Interstitial fibrosis/tubular atrophy (IFTA) is an important cause of kidney allograft loss; however, noninvasive markers to identify IFTA or guide antifibrotic therapy are lacking. Using angiotensin II (AngII) as the prototypical inducer of IFTA, we previously identified 83 AngII-regulated proteins in vitro. We developed mass spectrometry-based assays for quantification of 6 AngII signature proteins (bone marrow stromal cell antigen 1, glutamine synthetase [GLNA], laminin subunit beta-2, lysophospholipase I, ras homolog family member B, and thrombospondin-I [TSP1]) and hypothesized that their urine excretion will correlate with IFTA in kidney transplant patients. METHODS: Urine excretion of 6 AngII-regulated proteins was quantified using selected reaction monitoring and normalized by urine creatinine. Immunohistochemistry was used to assess protein expression of TSP1 and GLNA in kidney biopsies. RESULTS: The urine excretion rates of AngII-regulated proteins were found to be increased in 15 kidney transplant recipients with IFTA compared with 20 matched controls with no IFTA (mean log2[fmol/µmol of creatinine], bone marrow stromal cell antigen 1: 3.8 versus 3.0, P = 0.03; GLNA: 1.2 versus -0.4, P = 0.03; laminin subunit beta-2: 6.1 versus 5.4, P = 0.06; lysophospholipase I: 2.1 versus 0.6, P = 0.002; ras homolog family member B: 1.2 versus -0.1, P = 0.006; TSP1_GGV: 2.5 versus 1.9; P = 0.15; and TSP1_TIV: 2.0 versus 0.6, P = 0.0006). Receiver operating characteristic curve analysis demonstrated an area under the curve = 0.86 for the ability of urine AngII signature proteins to discriminate IFTA from controls. Urine excretion of AngII signature proteins correlated strongly with chronic IFTA and total inflammation. In a separate cohort of 19 kidney transplant recipients, the urine excretion of these 6 proteins was significantly lower following therapy with AngII inhibitors (P < 0.05). CONCLUSIONS: AngII-regulated proteins may represent markers of IFTA and guide antifibrotic therapies.

4.
Clin J Am Soc Nephrol ; 14(2): 213-223, 2019 02 07.
Artículo en Inglés | MEDLINE | ID: mdl-30647093

RESUMEN

BACKGROUND AND OBJECTIVES: FSGS and nephrotic syndrome studies have shown that single gene causes are more likely to be found in pediatric cases than adults. Consequently, many studies have examined limited gene panels in largely pediatric cohorts. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Whole-exome sequencing was performed in adults with FSGS diagnosed between 1976 and 2017 in the Toronto GN Registry. An expanded panel of 109 genes linked to FSGS, glomerular basement membrane abnormalities, as well as causes of pediatric ESKD including congenital abnormalities of the kidney and urinary tract (CAKUT) and nephronophthisis, were examined. RESULTS: The cohort was composed of 193 individuals from 179 families. Nearly half (49%) developed ESKD at a mean age of 47±17 years. The genetic diagnostic rate was 11%. Of definitely pathogenic variants, 55% were in COL4A (A3/A4/A5), 40% were in podocyte genes, and 5% were in CAKUT genes. Many, but not all individuals with COL4A definitely pathogenic variants had some evidence of glomerular basement membrane abnormalities. The estimated mean survival/age of kidney failure for individuals with COL4A definitely pathogenic variants was 58 years (95% confidence interval, 49 to 69), far later than what has been reported in the literature. Likely pathogenic variants were identified in an additional 9% of the cohort, with most in COL4A. Correlation with glomerular basement membrane morphology suggested a causal role for at least some of these likely pathogenic variants. CONCLUSIONS: Even with an expanded gene panel, we find that COL4A disorders are the leading monogenic cause in adults diagnosed with FSGS. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_01_15_CJASNPodcast_19_02_.mp3.

5.
Hypertension ; 73(3): 561-570, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30636551

RESUMEN

The proto-oncogene c-myb (and corresponding nuclear transcription factor, c-Myb) regulates the proliferation and differentiation of hematologic and vascular smooth muscle cells; however, the role of c-Myb in blood pressure regulation is unknown. Here, we show that mice homozygous for a hypomorphic c-myb allele ( c-myb h/h) conferring reduced c-Myb activity manifest reduced peripheral blood and kidney B220+ B-cells and have decreased systolic (104±2 versus 120±1 mm Hg; P<0.0001) and diastolic blood pressure (71±2 versus 83±1 mm Hg; P<0.0001) compared with WT (wild type) mice. Additionally, c-myb h/h mice had lower susceptibility to deoxycorticosterone acetate-salt experimental hypertension. Although cardiac (echocardiography) and resistance artery (perfusion myography) functions were normal, metabolic cage studies revealed that c-myb h/h mice had increased 24-hour urine output and sodium excretion versus WT. Reconstitution of WT mice with c-myb h/h bone marrow transplant and chimeric bone marrow transplant using mice lacking B-cells ( J H T; h/h>WT and h/h:J H T>WT, respectively) decreased blood pressure and increased 24-hour urine output compared with controls ( WT>WT; WT:J H T>WT). J H T mice also had decreased systolic (103±2 versus 115±1 mm Hg; P<0.0001) and diastolic blood pressure (71±2 versus 79±1; P<0.01) and increased 24-hour urine output versus WT. Real-time quantitative reverse transcription polymerase chain reaction of kidney medulla revealed reduced V2R (vasopressin receptor 2) expression in c-myb h/h and J H T mice. These data implicate B-cells in the regulation of V2R and its associated effects on salt and water handling and blood pressure homeostasis.


Asunto(s)
Linfocitos B/metabolismo , Presión Sanguínea/fisiología , Hipertensión/inmunología , Miocitos del Músculo Liso/metabolismo , Animales , Linfocitos B/patología , Diferenciación Celular , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Hipertensión/metabolismo , Hipertensión/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miocitos del Músculo Liso/patología , Proteínas Proto-Oncogénicas c-myb/biosíntesis , Proteínas Proto-Oncogénicas c-myb/genética , ARN/genética
6.
Clin Kidney J ; 11(3): 310-314, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29942494

RESUMEN

Cobalamin C (cblC) deficiency is the most commonly inherited inborn error of vitamin B12 metabolism. It is characterized by multisystem involvement with severe neurological, hematological, renal and cardiopulmonary manifestations. Disease is most commonly diagnosed early in the first decade of life. We report a case of a 20-year-old woman who developed severe pulmonary arterial hypertension while under nephrologic follow-up for chronic kidney disease. She had initially presented at 14 years of age with visual disturbance and acute renal failure and been diagnosed with thrombotic thrombocytopenic purpura on the basis of kidney biopsy findings of thrombotic microangiopathy and compatible ADAMTS13 (a disentegrin and metalloproteinase with a thrombospondin type 1 motif member 13). When cblC deficiency was eventually diagnosed, remarkable improvement in cardiopulmonary function was evident upon initiation of treatment. This case highlights the importance of a timely diagnosis and initiation of treatment for cblC deficiency. Clinical diagnosis may be challenged by asynchronous organ symptom presentation and by misleading laboratory tests, in this case: an initial low ADAMTS13. A simple test of plasma homocysteine level should be encouraged in cases of thrombotic microangiopathy and/or pulmonary artery hypertension.

8.
Transplantation ; 102(8): 1262-1270, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29683999

RESUMEN

BACKGROUND: Cold storage is poorly tolerated by kidney grafts retrieved after donation after circulatory death. It has been determined that normothermic ex vivo kidney perfusion (NEVKP) preservation decreases injury by minimizing cold ischemic storage. The impact of NEVKP on warm ischemic injury is unknown. METHODS: We compared pig kidneys retrieved after 30 minutes warm ischemia and immediate transplantation (no-preservation) with grafts that were exposed to 30 minutes of warm ischemia plus 8-hour NEVKP or plus 8-hour static cold storage (SCS). RESULTS: After transplantation, the NEVKP group demonstrated lower daily serum creatinine levels indicating better early graft function compared with no-preservation (P = 0.02) or SCS group (P < 0.001). In addition, NEVKP preserved grafts had a significantly lower grade of tubular injury and interstitial inflammation 30 minutes after reperfusion compared to grafts without any storage (injury score, NEVKP 1-2 vs no-preservation, 2-2, P = 0.029; inflammation score, NEVKP, 0-0.5 vs no-preservation, 1-2; P = 0.002), although it did not reach significance level when compared to the SCS group (injury score, 1-2, P = 0.071; inflammation score, 1-1; P = 0.071). Regeneration was assessed 30 minutes after reperfusion by Ki-67 staining. The NEVKP group demonstrated significantly higher number of Ki-67-positive cells: 9.2 ± 3.7 when compared with SCS group (3.9 ± 1.0, P = 0.015) and no-preservation group (4.2 ± 0.7, P = 0.04). CONCLUSIONS: In this porcine model of donation after circulatory death kidney transplantation NEVKP reduced kidney injury and improved graft function when compared with no-preservation. The results suggest that NEVKP does not cause additional damage to grafts during the preservation period, but may reverse the negative effects of warm ischemic insult itself and promotes regeneration.


Asunto(s)
Muerte , Trasplante de Riñón/métodos , Preservación de Órganos , Perfusión , Isquemia Tibia/efectos adversos , Animales , Aorta/patología , Isquemia Fría , Modelos Animales de Enfermedad , Riñón , Soluciones Preservantes de Órganos/farmacología , Regeneración , Daño por Reperfusión/fisiopatología , Porcinos , Factores de Tiempo
9.
Am J Kidney Dis ; 71(3): 441-445, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29198386

RESUMEN

Alport syndrome is a rare hereditary disorder caused by rare variants in 1 of 3 genes encoding for type IV collagen. Rare variants in COL4A5 on chromosome Xq22 cause X-linked Alport syndrome, which accounts for ∼80% of the cases. Alport syndrome has a variable clinical presentation, including progressive kidney failure, hearing loss, and ocular defects. Exome sequencing performed in 2 affected related males with an undefined X-linked glomerulopathy characterized by global and segmental glomerulosclerosis, mesangial hypercellularity, and vague basement membrane immune complex deposition revealed a COL4A5 sequence variant, a substitution of a thymine by a guanine at nucleotide 665 (c.T665G; rs281874761) of the coding DNA predicted to lead to a cysteine to phenylalanine substitution at amino acid 222, which was not seen in databases cataloguing natural human genetic variation, including dbSNP138, 1000 Genomes Project release version 01-11-2004, Exome Sequencing Project 21-06-2014, or ExAC 01-11-2014. Review of the literature identified 2 additional families with the same COL4A5 variant leading to similar atypical histopathologic features, suggesting a unique pathologic mechanism initiated by this specific rare variant. Homology modeling suggests that the substitution alters the structural and dynamic properties of the type IV collagen trimer. Genetic analysis comparing members of the 3 families indicated a distant relationship with a shared haplotype, implying a founder effect.


Asunto(s)
Colágeno Tipo IV/genética , Predisposición Genética a la Enfermedad , Nefritis Hereditaria/genética , Nefritis Hereditaria/patología , Linaje , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Biopsia con Aguja , Análisis Mutacional de ADN , Estudios de Seguimiento , Efecto Fundador , Pruebas Genéticas/métodos , Variación Genética , Humanos , Inmunohistoquímica , Masculino , Nefritis Hereditaria/diagnóstico , Nefritis Hereditaria/tratamiento farmacológico , Medición de Riesgo , Índice de Severidad de la Enfermedad , Esteroides/uso terapéutico , Adulto Joven
10.
Pediatr Nephrol ; 33(6): 991-993, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-28785983

RESUMEN

BACKGROUND: Sarcoidosis is a multisystem granulomatous disease of unknown etiology that rarely presents in childhood. Here, we report a case of pediatric sarcoidosis presenting with renal failure and hypercalcemia. CASE DIAGNOSIS/TREATMENT: A previously well 14-year-old Caucasian boy was admitted to the Hospital for Sick Children, Canada, for hypertension and renal failure following work-up by his family physician for initial concerns of growth failure. On admission, his weight was 35 kg (<3rd percentile), his height was 148 cm (≪3rd percentile), and his blood pressure was 154/116 mmHg (>99th percentile for height). Laboratory findings showed elevated creatinine (218 µmol/L), hypercalcemia (3.21 mmol/L), and normocytic anemia (hemoglobin 105 g/L). His further assessment showed a urinary concentrating defect with hypercalciuria (calcium/creatinine 1.76 mmol/mmol) and nephrocalcinosis on ultrasound. His eye examination showed uveitis with conjunctival biopsy remarkable for granulomas, which led to pursuit of a diagnosis of possible sarcoidosis. Angiotensin-converting enzyme was found to be high at 96 U/L, and he had a renal biopsy that was consistent with interstitial nephritis with granulomas. Treatment was started with prednisone leading to resolution of his hypercalcemia but persistence of his mild chronic kidney disease. CONCLUSIONS: This case represents an atypical presentation of a rare pediatric disease and highlights the spectrum of renal manifestations and treatment options in sarcoidosis.


Asunto(s)
Insuficiencia de Crecimiento/etiología , Hipercalcemia/etiología , Insuficiencia Renal/etiología , Sarcoidosis/diagnóstico , Adolescente , Diagnóstico Diferencial , Glucocorticoides/uso terapéutico , Humanos , Riñón/patología , Masculino , Prednisona/uso terapéutico , Sarcoidosis/complicaciones , Sarcoidosis/tratamiento farmacológico
11.
Pediatr Nephrol ; 33(6): 995-999, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-28785985

RESUMEN

BACKGROUND: Sarcoidosis is a multisystem granulomatous disease of unknown etiology that rarely presents in childhood. Here, we report a case of pediatric sarcoidosis, presenting with renal failure and hypercalcemia. CASE DIAGNOSIS/TREATMENT: A previously well 14-year-old Caucasian boy was admitted to the Hospital for Sick Children, Canada, for hypertension and renal failure following work-up by his family physician for initial concerns of growth failure. On admission, his weight was 35 kg (<3rd percentile), his height was 148 cm (<<3rd percentile), and his blood pressure was 154/116 mmHg (>99th percentile for height). Laboratory findings showed elevated creatinine (218 umol/L), hypercalcemia (3.21 mmol/L), and normocytic anemia (hemoglobin 105 g/L). His further assessment showed a urinary concentrating defect with hypercalciuria (calcium/creatinine 1.76 mmol/mmol) and nephrocalcinosis on ultrasound. His eye examination showed uveitis with conjunctival biopsy remarkable for granulomas, which led to pursuit of a diagnosis of possible sarcoidosis. Angiotensin Angiotensin-converting enzyme was found to be high at 96 U/L, and he had a renal biopsy that was consistent with interstitial nephritis with granulomas. Treatment was started with prednisone leading to resolution of his hypercalcemia but persistence of his mild chronic kidney disease. CONCLUSIONS: This case represents an atypical presentation of a rare pediatric disease and highlights the spectrum of renal manifestations and treatment options in sarcoidosis.


Asunto(s)
Insuficiencia de Crecimiento/etiología , Hipercalcemia/etiología , Insuficiencia Renal/etiología , Sarcoidosis/diagnóstico , Adolescente , Diagnóstico Diferencial , Humanos , Riñón/patología , Masculino , Sarcoidosis/complicaciones , Sarcoidosis/tratamiento farmacológico
12.
Am J Transplant ; 18(3): 580-589, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-28889600

RESUMEN

Normothermic ex vivo kidney perfusion (NEVKP) represents a novel approach for graft preservation and functional improvement in kidney transplantation. We investigated whether NEVKP also allows graft quality assessment before transplantation. Kidneys from 30-kg pigs were recovered in a model of heart-beating donation (group A) after 30 minutes (group B) or 60 minutes (group C) (n = 5/group) of warm ischemia. After 8 hours of NEVKP, contralateral kidneys were resected, grafts were autotransplanted, and the pigs were followed for 3 days. After transplantation, renal function measured based on peak serum creatinine differed significantly among groups (P < .05). Throughout NEVKP, intrarenal resistance was lowest in group A and highest in group C (P < .05). intrarenal resistance at the initiation of NEVKP correlated with postoperative renal function (P < .001 at NEVKP hour 1). Markers of acid-base homeostasis (pH, HCO3- , base excess) differed among groups (P < .05) and correlated with posttransplantation renal function (P < .001 for pH at NEVKP hour 1). Similarly, lactate and aspartate aminotransferase were lowest in noninjured grafts versus donation after circulatory death kidneys (P < .05) and correlated with posttransplantation kidney function (P < .001 for lactate at NEVKP hour 1). In conclusion, assessment of perfusion characteristics and clinically available perfusate biomarkers during NEVKP allows the prediction of posttransplantation graft function. Thus, NEVKP might allow decision-making regarding whether grafts are suitable for transplantation.


Asunto(s)
Trasplante de Riñón/métodos , Preservación de Órganos/métodos , Garantía de la Calidad de Atención de Salud/normas , Medición de Riesgo/métodos , Donantes de Tejidos/provisión & distribución , Recolección de Tejidos y Órganos/normas , Obtención de Tejidos y Órganos/normas , Animales , Masculino , Modelos Animales , Perfusión , Porcinos , Temperatura Ambiental , Recolección de Tejidos y Órganos/métodos
13.
Kidney Int ; 91(6): 1347-1361, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28249676

RESUMEN

Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase in the renin-angiotensin system that catalyzes the breakdown of angiotensin II to angiotensin 1-7. We have reported that ACE2 expression in the kidney is reduced in experimental Alport syndrome but the impact of this finding on disease progression has not been studied. Accordingly, we evaluated effects of murine recombinant ACE2 treatment in Col4a3 knockout mice, a model of Alport syndrome characterized by proteinuria and progressive renal injury. Murine recombinant ACE2 (0.5 mg/kg/day) was administered from four to seven weeks of age via osmotic mini-pump. Pathological changes were attenuated by murine recombinant ACE2 treatment which ameliorated kidney fibrosis as shown by decreased expression of COL1α1 mRNA, less accumulation of extracellular matrix proteins, and inhibition of transforming growth factor-ß signaling. Further, increases in proinflammatory cytokine expression, macrophage infiltration, inflammatory signaling pathway activation, and heme oxygenase-1 levels in Col4a3 knockout mice were also reduced by murine recombinant ACE2 treatment. Lastly, murine recombinant ACE2 influenced the turnover of renal ACE2, as it suppressed the expression of tumor necrosis factor-α converting enzyme, a negative regulator of ACE2. Thus, treatment with exogenous ACE2 alters angiotensin peptide metabolism in the kidneys of Col4a3 knockout mice and attenuates the progression of Alport syndrome nephropathy.


Asunto(s)
Riñón/efectos de los fármacos , Nefritis Hereditaria/tratamiento farmacológico , Peptidil-Dipeptidasa A/administración & dosificación , Albuminuria/tratamiento farmacológico , Albuminuria/etiología , Albuminuria/metabolismo , Angiotensinas/metabolismo , Animales , Autoantígenos/genética , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Colágeno Tipo IV/deficiencia , Colágeno Tipo IV/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Fibrosis , Predisposición Genética a la Enfermedad , Mediadores de Inflamación/metabolismo , Riñón/metabolismo , Riñón/patología , Masculino , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Nefritis Hereditaria/complicaciones , Nefritis Hereditaria/genética , Nefritis Hereditaria/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fenotipo , Proteínas Recombinantes/administración & dosificación , Transducción de Señal/efectos de los fármacos , Factor de Crecimiento Transformador beta1/metabolismo
14.
Circ Cardiovasc Interv ; 10(3): e004172, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-28258128

RESUMEN

BACKGROUND: The therapeutic potential of renal denervation (RDN) for arrhythmias has not been fully explored. Detailed mechanistic evaluation is in order. The objective of the present study was to determine the antiarrhythmic potential of RDN in a postinfarct animal model and to determine whether any benefits relate to RDN-induced reduction of sympathetic effectors on the myocardium. METHODS AND RESULTS: Pigs implanted with single-chamber implantable cardioverter defibrillators to record ventricular arrhythmias (VAs) were subjected to percutaneous coronary occlusion to induce myocardial infarction. Two weeks later, a sham or real RDN treatment was performed bilaterally using the St Jude EnligHTN basket catheter. Parameters of ventricular remodeling and modulation of cardio-renal sympathetic axis were monitored for 3 weeks after myocardial infarction. Histological analysis of renal arteries yielded a mean neurofilament score of healthy nerves that was significantly lower in the real RDN group than in sham controls; damaged nerves were found only in the real RDN group. There was a 100% reduction in the rate of spontaneous VAs after real RDN and a 75% increase in the rate of spontaneous VAs after sham RDN (P=0.03). In the infarcted myocardium, presence of sympathetic nerves and tissue abundance of neuropeptide-Y, an indicator of sympathetic nerve activities, were significantly lower in the RDN group. Peak and mean sinus tachycardia rates were significantly reduced after RDN. CONCLUSIONS: RDN in the infarcted pig model leads to reduction of postinfarction VAs and myocardial sympathetic effectors. This may form the basis for a potential therapeutic role of RDN in postinfarct VAs.


Asunto(s)
Frecuencia Cardíaca , Corazón/inervación , Riñón/irrigación sanguínea , Infarto del Miocardio/complicaciones , Miocardio/patología , Arteria Renal/inervación , Simpatectomía/métodos , Sistema Nervioso Simpático/cirugía , Taquicardia Ventricular/prevención & control , Animales , Modelos Animales de Enfermedad , Femenino , Masculino , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Miocardio/metabolismo , Factor de Crecimiento Nervioso/metabolismo , Neuropéptido Y/metabolismo , Sus scrofa , Sistema Nervioso Simpático/patología , Sistema Nervioso Simpático/fisiopatología , Taquicardia Ventricular/etiología , Taquicardia Ventricular/patología , Taquicardia Ventricular/fisiopatología , Factores de Tiempo
15.
Transplantation ; 101(4): 754-763, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27467537

RESUMEN

BACKGROUND: Donation after circulatory death (DCD) is current clinical practice to increase the donor pool. Deleterious effects on renal graft function are described for hypothermic preservation. Therefore, current research focuses on investigating alternative preservation techniques, such as normothermic perfusion. METHODS: We compared continuous pressure-controlled normothermic ex vivo kidney perfusion (NEVKP) with static cold storage (SCS) in a porcine model of DCD autotransplantation. After 30 minutes of warm ischemia, right kidneys were removed from 30-kg Yorkshire pigs and preserved with 8-hour NEVKP or in 4°C histidine-tryptophan-ketoglutarate solution (SCS), followed by kidney autotransplantation. RESULTS: Throughout NEVKP, electrolytes and pH values were maintained. Intrarenal resistance decreased over the course of perfusion (0 hour, 1.6 ± 0.51 mm per minute vs 7 hours, 0.34 ± 0.05 mm Hg/mL per minute, P = 0.005). Perfusate lactate concentration also decreased (0 hour, 10.5 ± 0.8 vs 7 hours, 1.4 ± 0.3 mmol/L, P < 0.001). Cellular injury markers lactate dehydrogenase and aspartate aminotransferase were persistently low (lactate dehydrogenase < 100 U/L, below analyzer range; aspartate aminotransferase 0 hour, 15.6 ± 9.3 U/L vs 7 hours, 24.8 ± 14.6 U/L, P = 0.298). After autotransplantation, renal grafts preserved with NEVKP demonstrated lower serum creatinine on days 1 to 7 (P < 0.05) and lower peak values (NEVKP, 5.5 ± 1.7 mg/dL vs SCS, 11.1 ± 2.1 mg/dL, P = 0.002). The creatinine clearance on day 4 was increased in NEVKP-preserved kidneys (NEVKP, 39 ± 6.4 vs SCS, 18 ± 10.6 mL/min; P = 0.012). Serum neutrophil gelatinase-associated lipocalin at day 3 was lower in the NEVKP group (1267 ± 372 vs 2697 ± 1145 ng/mL, P = 0.029). CONCLUSIONS: Continuous pressure-controlled NEVKP improves renal function in DCD kidney transplantation. Normothermic ex vivo kidney perfusion might help to decrease posttransplant delayed graft function rates and to increase the donor pool.


Asunto(s)
Funcionamiento Retardado del Injerto/prevención & control , Supervivencia de Injerto , Trasplante de Riñón/métodos , Riñón/cirugía , Preservación de Órganos/métodos , Perfusión/métodos , Choque , Animales , Aspartato Aminotransferasas/metabolismo , Biomarcadores/sangre , Isquemia Fría , Creatinina/sangre , Funcionamiento Retardado del Injerto/sangre , Funcionamiento Retardado del Injerto/patología , Funcionamiento Retardado del Injerto/fisiopatología , Glucosa/farmacología , Supervivencia de Injerto/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/fisiopatología , Trasplante de Riñón/efectos adversos , L-Lactato Deshidrogenasa/metabolismo , Ácido Láctico/metabolismo , Lipocalina 2/sangre , Masculino , Manitol/farmacología , Modelos Animales , Nefrectomía , Preservación de Órganos/efectos adversos , Soluciones Preservantes de Órganos/farmacología , Perfusión/efectos adversos , Cloruro de Potasio/farmacología , Presión , Procaína/farmacología , Sus scrofa , Factores de Tiempo , Trasplante Autólogo
16.
Am J Kidney Dis ; 69(3): 473-476, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-27856086

RESUMEN

Preapproval clinical trials examining the safety and efficacy of rosuvastatin demonstrated an increased incidence of proteinuria, hematuria, rhabdomyolysis, and other acute kidney injury of unknown cause at high doses. The latter cases manifested with urine sediment findings and in some cases, renal histology, indicating renal tubular injury in the absence of rhabdomyolysis. Despite these provocative findings, there have been very few reports in the literature regarding non-rhabdomyolysis-mediated acute kidney injury associated with high-dose rosuvastatin since its widespread introduction more than a decade ago, suggesting that it is either a rare entity or systematically underdiagnosed and under-reported. We present a case of renal tubular toxicity attributable to the initiation of rosuvastatin treatment at a dose of 40mg in a patient with no prior evidence of kidney disease. Tubular toxicity should be considered in cases of unexplained kidney injury in the setting of exposure to a potent statin such as rosuvastatin, particularly at high dose. The limited evidence suggests a good kidney prognosis following withdrawal of the agent in these cases.


Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Necrosis Tubular Aguda/inducido químicamente , Rosuvastatina Cálcica/efectos adversos , Femenino , Humanos , Persona de Mediana Edad
17.
Transplantation ; 100(9): 1862-70, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-27479157

RESUMEN

BACKGROUND: Hypothermic kidney storage causes preservation injury and is poorly tolerated by renal grafts. We investigated whether static cold storage (SCS) can be safely replaced with a novel technique of pressure-controlled normothermic ex vivo kidney perfusion (NEVKP) in heart-beating donor kidney transplantation. METHODS: Right kidneys were removed from 30 kg Yorkshire pigs in a model of heart-beating donation and either preserved in cold histidine-tryptophan-ketoglutarate solution for 8 hours (n = 5), or subjected to 8 hours of pressure-controlled NEVKP (n = 5) followed by renal heterotopic autotransplantation. RESULTS: During NEVKP, physiologic perfusion conditions were maintained with low intrarenal resistance and normal electrolyte and pH parameters. Aspartate aminotransferase and lactate dehydrogenase as injury markers were below the detectable analyzer range (<4 and <100 U/L, respectively). Perfusate lactate concentration decreased from baseline until the end of perfusion (10.38 ± 0.76 mmol/L vs 1.22 ± 0.26 mmol/L; P < 0.001). Posttransplantation, animals transplanted with NEVKP versus SCS grafts demonstrated similar serum creatinine peak levels (NEVKP, 2.0 ± 0.5 vs SCS 2.7 ± 0.7 mg/dL; P = 0.11) and creatinine clearance on day 10 (NEVKP, 65.9 ± 18.8 mL/min vs SCS 61.2 ± 15.6 mL/min; P = 0.74). After 10 days of follow-up, animals transplanted with NEVKP grafts had serum creatinine and blood urea nitrogen values comparable to their basal levels (P = 0.49 and P = 0.59), whereas animals transplanted with SCS grafts had persistently elevated serum creatinine and blood urea nitrogen when compared with basal levels (P = 0.01 and P = 0.03). CONCLUSIONS: Continuous pressure-controlled NEVKP is feasible and safe in good quality heart-beating donor kidney grafts. It maintains a physiologic environment and excellent graft function ex vivo during preservation without causing graft injury.


Asunto(s)
Trasplante de Riñón/métodos , Riñón/cirugía , Preservación de Órganos/métodos , Perfusión , Animales , Aspartato Aminotransferasas/metabolismo , Biomarcadores/metabolismo , Nitrógeno de la Urea Sanguínea , Isquemia Fría/efectos adversos , Creatinina/sangre , Estudios de Factibilidad , Glucosa/farmacología , Supervivencia de Injerto , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Trasplante de Riñón/efectos adversos , L-Lactato Deshidrogenasa/metabolismo , Ácido Láctico/metabolismo , Masculino , Manitol/farmacología , Modelos Animales , Nefrectomía , Preservación de Órganos/efectos adversos , Soluciones Preservantes de Órganos/farmacología , Perfusión/efectos adversos , Cloruro de Potasio/farmacología , Presión , Procaína/farmacología , Sus scrofa , Factores de Tiempo , Supervivencia Tisular , Trasplante Autólogo
18.
J Vis Exp ; (108): 53765, 2016 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-26967919

RESUMEN

Kidney transplantation is the treatment of choice for patients suffering from end-stage renal disease. It offers better life expectancy and higher quality of life when compared to dialysis. Although the last few decades have seen major improvements in patient outcomes following kidney transplantation, the increasing shortage of available organs represents a severe problem worldwide. To expand the donor pool, marginal kidney grafts recovered from extended criteria donors (ECD) or donated after circulatory death (DCD) are now accepted for transplantation. To further improve the postoperative outcome of these marginal grafts, research must focus on new therapeutic approaches such as alternative preservation techniques, immunomodulation, gene transfer, and stem cell administration. Experimental studies in animal models are the final step before newly developed techniques can be translated into clinical practice. Porcine kidney transplantation is an excellent model of human transplantation and allows investigation of novel approaches. The major advantage of the porcine model is its anatomical and physiological similarity to the human body, which facilitates the rapid translation of new findings to clinical trials. This article offers a surgical step-by-step protocol for an autotransplantation model and highlights key factors to ensure experimental success. Adequate pre- and postoperative housing, attentive anesthesia, and consistent surgical techniques result in favorable postoperative outcomes. Resection of the contralateral native kidney provides the opportunity to assess post-transplant graft function. The placement of venous and urinary catheters and the use of metabolic cages allow further detailed evaluation. For long-term follow-up studies and investigation of alternative graft preservation techniques, autotransplantation models are superior to allotransplantation models, as they avoid the confounding bias posed by rejection and immunosuppressive medication.


Asunto(s)
Fallo Renal Crónico/cirugía , Trasplante de Riñón/métodos , Donantes de Tejidos , Animales , Modelos Animales de Enfermedad , Masculino , Porcinos , Trasplante Autólogo
19.
J Am Soc Nephrol ; 27(10): 3117-3128, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-26961347

RESUMEN

Like many organs, the kidney stiffens after injury, a process that is increasingly recognized as an important driver of fibrogenesis. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are related mechanosensory proteins that bind to Smad transcription factors, the canonical mediators of profibrotic TGF-ß responses. Here, we investigated the role of YAP/TAZ in the matrix stiffness dependence of fibroblast responses to TGF-ß In contrast to growth on a stiff surface, fibroblast growth on a soft matrix led to YAP/TAZ sequestration in the cytosol and impaired TGF-ß-induced Smad2/3 nuclear accumulation and transcriptional activity. YAP knockdown or treatment with verteporfin, a drug that was recently identified as a potent YAP inhibitor, elicited similar changes. Furthermore, verteporfin reduced YAP/TAZ levels and decreased the total cellular levels of Smad2/3 after TGF-ß stimulation. Verteporfin treatment of mice subjected to unilateral ureteral obstruction similarly reduced YAP/TAZ levels and nuclear Smad accumulation in the kidney, and attenuated renal fibrosis. Our data suggest that organ stiffening cooperates with TGF-ß to induce fibrosis in a YAP/TAZ- and Smad2/3-dependent manner. Interference with this YAP/TAZ and TGF-ß/Smad crosstalk likely underlies the antifibrotic activity of verteporfin. Finally, through repurposing of a clinically used drug, we illustrate the therapeutic potential of a novel mechanointerference strategy that blocks TGF-ß signaling and renal fibrogenesis.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/fisiología , Riñón/patología , Fosfoproteínas/fisiología , Proteína Smad2/fisiología , Proteína smad3/fisiología , Factores de Transcripción/fisiología , Factor de Crecimiento Transformador beta/fisiología , Animales , Proteínas de Ciclo Celular , Fibrosis/etiología , Masculino , Ratones , Ratones Endogámicos C57BL , Transducción de Señal
20.
J Am Soc Nephrol ; 27(9): 2609-15, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-26869008

RESUMEN

Fibrosis and inflammation are closely intertwined injury pathways present in nearly all forms of CKD for which few safe and effective therapies exist. Slit glycoproteins signaling through Roundabout (Robo) receptors have been described to have anti-inflammatory effects through regulation of leukocyte cytoskeletal organization. Notably, cytoskeletal reorganization is also required for fibroblast responses to TGF-ß Here, we examined whether Slit2 also controls TGF-ß-induced renal fibrosis. In cultured renal fibroblasts, which we found to express Slit2 and Robo-1, the bioactive N-terminal fragment of Slit2 inhibited TGF-ß-induced collagen synthesis, actin cytoskeletal reorganization, and Smad2/3 transcriptional activity, but the inactive C-terminal fragment of Slit2 did not. In mouse models of postischemic renal fibrosis and obstructive uropathy, treatment with N-terminal Slit2 before or after injury inhibited the development of renal fibrosis and preserved renal function, whereas the C-terminal Slit2 had no effect. Our data suggest that administration of recombinant Slit2 may be a new treatment strategy to arrest chronic injury progression after ischemic and obstructive renal insults by not only attenuating inflammation but also, directly inhibiting renal fibrosis.


Asunto(s)
Fibroblastos/efectos de los fármacos , Fibroblastos/fisiología , Péptidos y Proteínas de Señalización Intercelular/farmacología , Péptidos y Proteínas de Señalización Intercelular/uso terapéutico , Enfermedades Renales/prevención & control , Riñón/patología , Proteínas del Tejido Nervioso/farmacología , Proteínas del Tejido Nervioso/uso terapéutico , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Factor de Crecimiento Transformador beta/fisiología , Animales , Fibrosis/prevención & control , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Recombinantes
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