RESUMEN
OBJECTIVES: The once-daily prolonged-release formulation of tacrolimus (tacrolimus QD) is expected to demonstrate equivalent efficacy and safety to the twice-daily formulation (tacrolimus BID). We reviewed the 1-year outcomes of tacrolimus QD in de novo renal transplant. MATERIALS AND METHODS: We reviewed 50 de novo renal transplant patients assigned in a nonrandomized fashion to either tacrolimus QD (n=23, historic control group) or tacrolimus BID (n=27). Other immunosuppressive drugs used in both groups included mycophenolate mofetil, basiliximab, and steroids. We evaluated trough levels, required dosages, renal function, rejection rates, and episodes of infection within 1 year after transplant. RESULTS: Trough levels of both drugs varied during the perioperative periods, but subsequently stabilized in both groups. There was a tendency toward a slow elevation and a higher dosage requirement in the tacrolimus QD group, compared with the tacrolimus BID group in the early stages, though the required dosages decreased steadily. The rejection rate in the tacrolimus QD group was low, and only 1 patient experienced subclinical rejection. No severe infectious adverse events were observed. CONCLUSIONS: Patients taking tacrolimus QD tended to have lower trough levels and require higher dosages than those taking tacrolimus BID during the early posttransplant period, though the differences decreased with increasing time after transplant. Tacrolimus QD can be administered with excellent efficacy and safety in de novo renal transplant recipients.
Asunto(s)
Inmunosupresores/administración & dosificación , Trasplante de Riñón , Tacrolimus/administración & dosificación , Preparaciones de Acción Retardada , Estudios de Seguimiento , Rechazo de Injerto , Humanos , Inmunosupresores/farmacocinética , Estudios Retrospectivos , Tacrolimus/farmacocinética , Resultado del TratamientoRESUMEN
BACKGROUND: Accumulating evidence suggests that mineralocorticoid receptor (MR) blockade effectively reduces proteinuria in diabetic nephropathy although the renin-angiotensin-aldosterone system is generally suppressed in diabetes. The present study was designed to confirm the antiproteinuric effect of MR blockade in diabetic rats and elucidate its mechanism. METHODS: The present study investigated whether MR blockade inhibits hyperglycemia-induced podocyte injury, focusing on the involvement of reactive oxygen species (ROS) production, in diabetic rats and cultured podocytes. Sprague-Dawley rats were divided into three groups: control, streptozotocin (STZ; 75 mg/kg)-injected diabetic and STZ treated with spironolactone (SPL; 50 mg/kg/day) and sacrificed after 8, 16 and 24 weeks. RESULTS: Rats gradually developed proteinuria from 8 weeks after induction of diabetes. Immunostaining for Wilms' tumor-1 (WT1) and synaptopodin, markers of podocytes, was attenuated, whereas immunostaining for desmin, a marker of podocyte damage, and 8-hydroxy-2'-deoxyguanosine, a marker of oxidative stress, was up-regulated in the glomeruli of diabetic rats. Diabetic rats showed hypoaldosteronemia compared to the control, whereas SPL decreased proteinuria, ROS production and podocyte damage. To elucidate the paradox between hypoaldosteronemia and effect of SPL under hyperglycemia, the role of high glucose in MR activation and podocyte injury was explored. In cultured MR-expressing podocytes, high glucose significantly enhanced Sgk1 expression, activated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and ROS production and induced podocyte apoptosis. All these effects were inhibited by SPL. CONCLUSION: We conclude that hyperglycemia in diabetes, independent of plasma aldosterone concentration, induces podocyte injury through MR-mediated ROS production and leads to proteinuria. SPL inhibits hyperglycemia-induced podocyte injury by attenuating ROS production.
Asunto(s)
Diabetes Mellitus Experimental/prevención & control , Hiperglucemia/prevención & control , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Podocitos/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Espironolactona/uso terapéutico , Animales , Western Blotting , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Hiperglucemia/metabolismo , Hiperglucemia/patología , Masculino , NADPH Oxidasas/genética , NADPH Oxidasas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Podocitos/metabolismo , Podocitos/patología , Proteinuria/metabolismo , Proteinuria/patología , Proteinuria/prevención & control , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Sistema Renina-Angiotensina/efectos de los fármacos , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
BACKGROUND: Theoretically, an early protocol biopsy (PB) serves to detect subclinical rejection (SCR), allowing early treatment and prevention of acute rejection (AR) and chronic graft injuries. In this retrospective study, we investigated the incidence of biopsy-proven AR (BPAR) and the usefulness of a 3-month PB in detecting SCR in kidney transplant (KT) and simultaneous pancreas-kidney transplant (SPKT) recipients who received triple immunosuppression and basiliximab. METHODS: Between January 2007 and September 2009, 116 patients received transplantation (KT = 112, SPKT = 4). In August 2008, we changed our PB policy and started to collect PB after 3 months instead of a pre-discharge biopsy performed 1 month after transplantation. Here we compare the incidence of SCR (defined as Banff grade Ia or higher) between the pre-discharge PB group and the 3-month PB group. PB was obtained from 41 patients before discharge (pre-discharge PB group), and from 49 patients 3 months after transplantation (3-month PB group). RESULTS: Among all recipients, 21 patients were diagnosed with BPAR (estimated incidence of BPAR 20.1%); including 13 (62.0%) diagnosed from 31 to 180 postoperative days (POD), and only 3 (14.3%) within 30 POD. The incidence of BPAR was not different between the two groups (19.5 and 20.8%, respectively); however, 4 of 8 recipients in the 3-month PB group were diagnosed with SCR, compared to none in the pre-discharge PB group (P < 0.05). CONCLUSION: Since the use of triple immunosuppression and basiliximab delayed the onset of AR, we recommend that in order to detect SCR, PB should be obtained 3 months postoperatively.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Rechazo de Injerto/prevención & control , Trasplante de Riñón/métodos , Proteínas Recombinantes de Fusión/uso terapéutico , Adulto , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Basiliximab , Biopsia , Ciclosporina/uso terapéutico , Femenino , Humanos , Terapia de Inmunosupresión/métodos , Inmunosupresores/uso terapéutico , Trasplante de Riñón/patología , Masculino , Persona de Mediana Edad , Trasplante de Páncreas/métodos , Trasplante de Páncreas/patología , Estudios Retrospectivos , Rituximab , Tacrolimus/uso terapéuticoRESUMEN
The donor was 63-yr-old woman with subarachnoid hemorrhage. As she developed severe hypotension for more than four h before cardiac arrest, we biopsied the grafts and decided to transplant those kidneys. Recipient 1 was a 23-yr-old man on 13-yr dialysis program. After 19 d of delayed graft function (DGF), we discontinued hemodialysis (HD). However, the decrease in serum creatinine (sCr) was poor. The minimum sCr was 4.3 mg/dL on post-operative day (POD) 40, and increased to 6.5 mg/dL. The contralateral graft was transplanted to a 61-yr-old man (recipient 2) with 18-yr HD. After 15 d of DGF period, sCr decreased gradually and has been stable at 1.9 mg/dL. In recipient 1, graft biopsies performed on POD 15, 69, and 110, revealed progressive interstitial fibrosis and tubular atrophy (IF/TA) without evidences of acute rejection, tacrolimus associated injury, reflux nephropathy, or viral nephropathy. The second biopsy on POD 69 showed typical findings of acute tubular necrosis. We compared the clinical courses of the two recipients because certain features of recipient 1, such as age, duration of HD, total ischemic time, and body size were advantageous, whereas graft function was poorer than that in recipient 2. Recipient 1 developed severe anemia following the dissociation of graft function from recipient 2. In this case, posttransplant anemia and lower blood pressure might promote IF/TA through persistent ischemic tubular damage, and positive CMV antigenemia and its treatment could promote anemia. Especially in the kidney allograft from a marginal donor, we should consider various factors to obtain a better graft outcome.
Asunto(s)
Trasplante de Riñón/efectos adversos , Riñón/patología , Nefritis Intersticial/etiología , Daño por Reperfusión/fisiopatología , Adulto , Biopsia , Creatinina/sangre , Funcionamiento Retardado del Injerto/fisiopatología , Femenino , Fibrosis , Humanos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Nefritis Intersticial/fisiopatología , Diálisis Renal , Donantes de Tejidos , Trasplante Homólogo , Adulto JovenRESUMEN
A 23-year-old man was admitted to our hospital for fatigue, anorexia, proteinuria, and peripheral edema. Proteinuria was first pointed out at the age of 15, but no further studies were performed. Six years prior to admission, the patient noted becoming easily fatigued. Laboratory tests on admission showed marked peripheral eosinophilia (29.2%, count: 1,071/microL) and proteinuria. Endocrinological studies revealed isolated adrenocorticotropic hormone deficiency with primary hypothyroidism, but a lack of autoimmune thyroiditis. Renal biopsy showed focal segmental glomerulosclerosis. Hydrocortisone therapy (30 mg/day) for isolated adrenocorticotropic hormone deficiency resulted in marked improvement of adrenal and thyroid functions, and amelioration of proteinuria (from 2.8 to 1.0 g/day) over a two-month period. Renal function remains normal at five years after the start of hydrocortisone treatment. The findings suggest that both hydrocortisone therapy and normalized thyroid hormone status played a pivotal role in the improvement of proteinuria associated with focal segmental glomerulosclerosis.
Asunto(s)
Insuficiencia Suprarrenal/sangre , Glomeruloesclerosis Focal y Segmentaria/sangre , Hipotiroidismo/sangre , Hormona Adrenocorticotrópica/deficiencia , Glomeruloesclerosis Focal y Segmentaria/tratamiento farmacológico , Humanos , Hidrocortisona/uso terapéutico , Masculino , Pruebas de Función Hipofisaria , Proteinuria/sangre , Proteinuria/etiología , Adulto JovenRESUMEN
A 54-year-old woman was transferred to our hospital with disseminated intravascular coagulation, and was treated with heparin. On hospitalization day 13, she developed lower abdominal pain and mass followed by circulatory shock. She became oliguric and laboratory tests showed serum creatinine of 3.5 mg/dL and hemoglobin of 7.4 g/dL. Computed tomography showed hematoma in the left rectus sheath, compressing the urinary bladder exteriorly, which resulted in worsening of bilateral hydronephrosis. Conservative treatment resulted in resolution of the rectus sheath hematoma and improvement of renal function. Rectus sheath hematoma can be treated conservatively without surgical intervention even in complicated cases.
Asunto(s)
Anticoagulantes/efectos adversos , Hematoma/inducido químicamente , Hematoma/complicaciones , Heparina/efectos adversos , Choque Hemorrágico/etiología , Enfermedades de la Vejiga Urinaria/etiología , Anticoagulantes/administración & dosificación , Esquema de Medicación , Femenino , Hematoma/diagnóstico por imagen , Heparina/administración & dosificación , Humanos , Persona de Mediana Edad , Recto del Abdomen/patología , Tomografía Computarizada por Rayos X , Enfermedades de la Vejiga Urinaria/diagnóstico por imagenRESUMEN
National Fukuoka-Higashi Medical Center, Koga, Japan A 63-yr-old Japanese woman on 18-yr hemodialysis (HD) program underwent cadaveric kidney transplantation from non-heart beating donor. Pre-transplant lymphocytotoxicity test was negative, but flow cytometric cross-match and flow-cytometric panel reactive antibody (PRA) screening tests were positive. Flow-PRA single-antigen test revealed several anti-HLA antibodies including donor-specific antibody (DSA). She was treated with plasma exchange (PEX) and rituximab to prevent antibody-mediated rejection (AMR). Urinary output increased from post-operative day (POD) 5 and HD was discontinued from POD8. Graft biopsy performed on POD11 showed severe peritubular capillaritis (PTCitis), numerous polymorphonuclear neutrophils (PMNs), and moderate glomerulitis. Although C4d immunostaining on PTC was negative, the case was diagnosed as subclinical AMR based on the presence of pre-transplant DSA and PTCitis with predominant PMNs. The patient was treated with additional PEX and rituximab, which increased urinary output and reduced serum creatinine (sCr). Graft biopsy repeated on POD39 showed persistent severe PTCitis, moderate interstitial infiltration, and mild tubulitis. C4d on PTC was negative again. The patient was discharged from the hospital on POD40. During the seven months follow-up at the outpatient clinic, the sCr level has shown a slight increase. In this case, the patient had DSA, which can be detected only by flow-PRA. In both graft biopsies, C4d on PTC was negative despite the presence of severe PTCitis, and thus the diagnosis of AMR could not be established. However, the significance of subclinical PTCitis is reported perhaps as an early marker for chronic AMR and to emphasize the importance of close follow-up.
Asunto(s)
Biopsia/métodos , Capilares/patología , Rechazo de Injerto/patología , Antígenos HLA/inmunología , Trasplante de Riñón/patología , Túbulos Renales/irrigación sanguínea , Vasculitis/patología , Femenino , Citometría de Flujo , Rechazo de Injerto/inmunología , Humanos , Trasplante de Riñón/inmunología , Túbulos Renales/patología , Persona de Mediana Edad , Vasculitis/inmunologíaRESUMEN
A 40-year-old man was transferred to our hospital because of severe anasarca. He was a heavy drinker for more than 20 years, and diagnosed with diabetes mellitus 8 years earlier and treated with retinal photocoagulation 8 months earlier. He reported loss of appetite after divorce 10 months prior to admission. On admission, he presented with systemic edema and dyspnea. Chest radiography showed massive pleural effusion and cardiomegaly. Serum total protein was 5.6 g/dl, albumin 2.6 g/dl, and urinary protein excretion was 5.3 g/day. Glucose tolerance test showed normal pattern. Ultrafiltration and continuous hemofiltration resulted in loss of 40 kg body weight in 5 days. Echocardiography revealed high-output heart failure and blood tests showed low serum thiamine level of 12 ng/ml (normal, >28 ng/ml). Accordingly, the diagnosis was established as beriberi heart disease complicated with nephrotic syndrome. Treatment with 50 mg/day thiamine intravenously and 80 mg/day furosemide resulted in increase in urine output, decrease in cardiac output, resolution of pulmonary effusion, and about 70 kg body weight loss. Percutaneous renal biopsy showed nodular glomerulosclerosis, mesangial matrix expansion, and thickening of glomerular basement membrane (GBM). Immunofluorescence study showed no glomerular deposition of immunoglobulin or complement. Electron microscopy showed GBM thickening and mesangial matrix deposition without electron-dense deposits or fibrils. These findings were compatible with diabetic glomerulosclerosis. In this patient, extreme malnutrition altered glucose tolerance but, on the other hand, nephrotic syndrome associated with diabetic nephropathy made the diagnosis of beriberi heart disease difficult.
Asunto(s)
Beriberi/complicaciones , Nefropatías Diabéticas/complicaciones , Edema/etiología , Cardiopatías , Adulto , Beriberi/patología , Diabetes Mellitus/patología , Nefropatías Diabéticas/patología , Cardiopatías/complicaciones , Cardiopatías/etiología , Humanos , Glomérulos Renales/patología , MasculinoRESUMEN
Diabetic nephropathy (DN) associated with type 2 diabetes is the most common cause of end-stage renal disease (ESRD) and a serious health issue in the world. Currently, molecular basis for DN has not been established and only limited clinical treatments are effective in abating the progression to ESRD associated with DN. Here we found that diabetic db/db mice which lack the leptin receptor signaling can be used as a model of ESRD associated with DN. We demonstrated that p70S6-kinase was highly activated in mesangial cells in diabetic obese db/db mice. Furthermore, systemic administration of rapamycin, a specific and potent inhibitor of mTOR, markedly ameliorated pathological changes and renal dysfunctions. Moreover, rapamycin treatment shows a significant reduction in fat deposits and attenuates hyperinsulinemia with few side effects. These results indicate that mTOR activation plays a pivotal role in the development of ESRD and that rapamycin could be an effective therapeutic agent for DN.
Asunto(s)
Proteínas Portadoras/metabolismo , Diabetes Mellitus Tipo 2/enzimología , Nefropatías Diabéticas/enzimología , Fallo Renal Crónico/enzimología , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Sirolimus/uso terapéutico , Animales , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/tratamiento farmacológico , Riñón/efectos de los fármacos , Riñón/fisiopatología , Fallo Renal Crónico/tratamiento farmacológico , Fallo Renal Crónico/etiología , Ratones , Ratones Endogámicos , Mapeo Restrictivo , Proteínas Quinasas S6 Ribosómicas 70-kDa/biosíntesis , Serina-Treonina Quinasas TORRESUMEN
MRL/lpr mice develop a systemic autoimmune disease that is reminiscent of systemic lupus erythematosus (SLE) and Sjögren's syndrome in humans. To investigate the role of IL-27 in the development of autoimmune disorders in MRL/lpr mice, we disrupted the EBV-induced gene 3 (EBI3), which is a subunit of IL-27. Consequently, the pathophysiology of glomerulonephritis and sialadenitis, which develops in MRL/lpr mice, was drastically changed. EBI3-/- MRL/lpr mice developed disease that resembles human membranous glomerulonephritis (MGN), not diffuse proliferative glomerulonephritis (DPGN), with a predominance of IgG1 in glomerular deposits, and different type sialadenitis from Sjögren's syndrome, with IgG1 producing plasma cell infiltration in salivary glands, accompanied by increased IgG1 and IgE in the sera. T cells in these mice displayed significantly reduced IFN-gamma production along with elevated IL-4 expression. Loss of EBI3 thus favors Th2-type autoimmune responses, suggesting that the Th1/Th2 balance may be a pivotal determinant of phenotypes of human autoimmune diseases.
Asunto(s)
Enfermedades Autoinmunes/patología , Autoinmunidad/inmunología , ADN/genética , Glomerulonefritis Membranosa/patología , Mutación , Receptores de Citocinas/deficiencia , Sialadenitis/patología , Animales , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Genotipo , Glomerulonefritis Membranosa/genética , Glomerulonefritis Membranosa/inmunología , Inmunoglobulina E/inmunología , Inmunoglobulina E/metabolismo , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Interferón gamma/biosíntesis , Interleucina-4/biosíntesis , Glomérulos Renales/inmunología , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos MRL lpr , Antígenos de Histocompatibilidad Menor , Reacción en Cadena de la Polimerasa , Receptores de Citocinas/genética , Sialadenitis/genética , Sialadenitis/inmunología , Linfocitos T/inmunología , Células TH1/inmunología , Células Th2/inmunologíaRESUMEN
Thirteen years ago, a 65-year-old woman was diagnosed to have chronic active hepatitis with hepatitis C virus. After starting interferon alpha administration, she noticed edema and hypoalbuminemia. Renal biopsy revealed mesangial proliferation with focal endocapillary proliferation, and double contour of the glomerular basement membrane due to mesangial interposition. Interferon alpha was discontinued, and proteinuria and edema gradually decreased. She was re-admitted due to a relapse of proteinuria 8 years later. Biopsy revealed moderate mesangial and endcapillary proliferation presenting a lobular pattern, in addition to the presence of hyaline thrombi. Granular staining of immunoglobulin M and of C3 in capillary walls were detected. Since cryoglobulinemia was positive, a final diagnosis of cryoglobulinemic membranoproliferative glomerulonephritis was made. Prednisolone was started with an initial dose of 20 mg/day. Proteinuria and hypoalbuminemia improved, and prednisolone was tapered to 5 mg/day 9 months after the 2nd renal biopsy. The hepatitis C virus-RNA titer fluctuated.
Asunto(s)
Glomerulonefritis Membranoproliferativa/complicaciones , Glomerulonefritis Membranoproliferativa/tratamiento farmacológico , Glucocorticoides/uso terapéutico , Hepatitis C Crónica/complicaciones , Prednisolona/uso terapéutico , Anciano , Femenino , Humanos , Inducción de RemisiónRESUMEN
Chronic inhibition of nitric oxide synthase by N(omega)-nitro- L-arginine methyl ester (L-NAME) causes progressive renal injury with systemic hypertension and interstitial macrophage infiltration. We have previously shown that there is local activation of the renin-angiotensin-aldosterone system in the renal cortex as a major pathogenic feature of macrophage infiltration. In this study, we measured the effects of the aldosterone antagonist, spironolactone, on renal injury in L-NAME-treated male Wistar rats. After 12 weeks of L-NAME-treatment, rats had increased systolic blood pressure, urinary protein excretion, and serum creatinine and histological analysis showed glomerulosclerosis, interstitial fibrosis, and macrophage infiltration. Treatment with spironolactone significantly prevented these renal changes, whereas treatment with hydralazine had no effect. The cortical expression of osteopontin was significantly elevated in L-NAME-treated rats, and expression of its mRNA significantly correlated with the number of infiltrating macrophages and degree of interstitial fibrosis. Spironolactone treatment markedly suppressed osteopontin expression. Our results suggest that reduced nitric oxide bioavailability caused renal inflammation and fibrosis through an aldosterone receptor-dependent mechanism associated with osteopontin expression independent of its systemic hemodynamic effects.
Asunto(s)
Inflamación/prevención & control , Enfermedades Renales/prevención & control , NG-Nitroarginina Metil Éster/efectos adversos , Animales , Fibrosis , Hemodinámica , Inflamación/tratamiento farmacológico , Enfermedades Renales/inducido químicamente , Enfermedades Renales/tratamiento farmacológico , Masculino , Óxido Nítrico/metabolismo , Osteopontina/análisis , Osteopontina/genética , Sustancias Protectoras , ARN Mensajero/análisis , Ratas , Ratas Wistar , Receptores de Mineralocorticoides/fisiología , Espironolactona/farmacologíaRESUMEN
A 42-year-old woman was admitted to Kyushu University hospital because of 6 months' history of bilateral leg edema. Upon admission, ascites and pleural effusion as well as systemic edema were noted. Laboratory tests revealed hypoalbuminemia of 1.5 g/dl and massive proteinuria of 10 g/day. She was diagnosed with nephrotic syndrome. Renal biopsy revealed diffuse thickening of the glomerular basement membrane (GBM) and a crescent-like extracapillary lesion with segmental sclerosis in four of 11 glomeruli. Immunoglobulins and complements were negative by immunofluorescence examination. Therefore, we diagnosed this as focal segmental glomerulosclerosis (FSGS) rather than membranous nephropathy. Using an electron microscope, we observed a thickening of the GBM with numerous intramembranous vesicle-like microstructures and an infolding of the podocyte into the GBM. Since the microstructures were partly demarcated by a unit membrane and some of them were located very closely to the infolded podocyte, we speculated that the microstructures were derived from the podocyte. The unique electron microscopic finding of our case is a disease entity rather than a reactive phenomenon.
Asunto(s)
Membrana Basal Glomerular/ultraestructura , Glomeruloesclerosis Focal y Segmentaria/patología , Podocitos/ultraestructura , Adulto , Femenino , Membrana Basal Glomerular/patología , Humanos , Microscopía Electrónica , Microesferas , Podocitos/patologíaRESUMEN
AIMS: The tumor suppressor protein p53 plays a critical role as a determinant of cell survival when cells are exposed to various toxic stresses, by preventing growth arrest, replication of damaged DNA, and apoptosis. A novel p53-dependent proapoptotic gene, Puma (p53 upregulated modulator of apoptosis) is thought to participate in this process. Recently, p53 was reported to play an essential role in cisplatin-induced renal tubular cell (RTC) death. The objective of the present study was to elucidate the roles of p53 and Puma in cisplatin-induced RTC death. MAIN METHODS: We examined the in vivo expression of p53 and Puma-alpha in the kidney and evaluated the modification of Puma-alpha expression and RTC death by in vitro treatment with pifithrin-alpha (PFT-alpha), a specific p53 inhibitor, or Puma-alpha-specific small interfering RNA (siRNA). KEY FINDINGS: While no immunoreactivity for anti-p53- and anti-Puma-alpha antibody was detected in the control rat kidney, de novo expression of p53 and Puma-alpha was identified in the proximal tubular cells of the outer medulla at 6 h after cisplatin injection. Upregulation of these proteins preceded severe RTC injury. In vitro experiments revealed that PFT-alpha inhibited upregulation of Puma-alpha, and inhibition of Puma-alpha, either by PFT-alpha or by Puma-alpha-specific siRNA, decreased RTC death induced by 24-h cisplatin exposure. SIGNIFICANCE: Our results indicated that p53 activation mediated cisplatin-induced RTC death through upregulation of Puma, and suggested that inhibition of p53 and Puma is beneficial for the prevention and treatment of cisplatin-induced acute renal failure.
Asunto(s)
Antineoplásicos/farmacología , Proteínas Reguladoras de la Apoptosis/antagonistas & inhibidores , Proteínas Reguladoras de la Apoptosis/fisiología , Cisplatino/farmacología , Genes p53/efectos de los fármacos , Túbulos Renales/efectos de los fármacos , Actinas/metabolismo , Animales , Muerte Celular/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Gliceraldehído-3-Fosfato Deshidrogenasas/metabolismo , Inmunohistoquímica , Túbulos Renales/citología , L-Lactato Deshidrogenasa/metabolismo , Masculino , ARN Interferente Pequeño/farmacología , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Activación Transcripcional/efectos de los fármacosRESUMEN
A 52-year-old Japanese female was admitted to our hospital for microhematuria, proteinuria and progressive renal dysfunction. Two years prior to admission, she was diagnosed with lung adenocarcinoma and multiple bone and brain metastases, and was treated with gefitinib (250 mg/day). Treatment for 6 months induced partial response with 30% regression of the primary lung tumor, and resolution of metastatic tumors. After confirmation of the partial remission state, we performed percutaneous renal biopsy. Glomeruli showed mild to moderate mesangial proliferation, segmental endocapillary proliferation and occasional fibrocellular crescent formation. In addition, severe interstitial fibrosis and tubular atrophy relative to the degree of glomerular sclerosis were noted. Immunofluorescence microscopy showed predominant IgA deposition in the mesangial area. Electron microscopy revealed subepithelial and paramesangial electron-dense deposits. In consideration of the prognosis of lung cancer and complication of immunosuppressive treatment, we continued gefitinib only and closely followed-up the clinical course in the outpatient clinic. Sixteen months later, she continued to have proteinuria and microhematuria, and the severity of renal dysfunction was still the same. However, the lung cancer started to increase in size. This is quite an unusual case presenting histologically with tubulointerstitial nephritis and IgA nephropathy in a patient on long-term treatment with gefitinib.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Glomerulonefritis por IGA/inducido químicamente , Neoplasias Pulmonares/tratamiento farmacológico , Nefritis Intersticial/inducido químicamente , Quinazolinas/efectos adversos , Quinazolinas/uso terapéutico , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Biopsia , Relación Dosis-Respuesta a Droga , Femenino , Gefitinib , Glomerulonefritis por IGA/diagnóstico , Glomerulonefritis por IGA/patología , Humanos , Riñón/patología , Persona de Mediana Edad , Nefritis Intersticial/diagnóstico , Nefritis Intersticial/patologíaRESUMEN
OBJECTIVE: To determine whether innate receptor signals play an important role in the development of autoimmune nephritis in MRL/lpr mice, an experimental model of lupus nephritis. METHODS: MyD88 is a critical adaptor that is involved in signaling pathways through all of the Toll-like receptors (TLRs) except TLR-3. We therefore generated MyD88-knockout (MyD88-KO) MRL/lpr mice and examined them for histopathologic changes in the kidneys, cumulative survival rates, extent of lymphadenopathy and splenomegaly, serum chemistry, and immunologic parameters. In addition, to define the role of the MyD88-independent pathway in autoimmune nephritis, we injected MyD88-KO MRL/lpr mice intraperitoneally with either poly(I-C) (50 or 100 microg per mouse) or phosphate buffered saline and examined them for survival as well as for histopathologic, serologic, and immunologic parameters. RESULTS: In comparison with wild-type mice, MyD88-KO MRL/lpr mice exhibited a prolonged lifespan, with no apparent development of autoimmune nephritis. Their kidneys showed no glomerular cell proliferation or crescent formation, along with a drastic decrease in the mesangial matrix. Lymphadenopathy and splenomegaly were less pronounced. Serum titers of anti-double-stranded DNA (anti-dsDNA) and production of cytokines, including interferon-alpha (IFNalpha), interleukin-12 (IL-12), IL-6, and IFNgamma, in splenocytes were significantly reduced in MyD88-KO MRL/lpr mice. Interestingly, MyD88-KO MRL/lpr mice that had been treated with the MyD88-independent TLR-3 ligand poly(I-C) showed an almost complete reversion to the features of wild-type mice, demonstrating crescentic glomerulonephritis, with significant elevation of serum anti-dsDNA titers and increased cytokine production in splenocytes. CONCLUSION: The findings indicate that both MyD88-dependent and MyD88-independent innate signals play a crucial role in the development of autoimmune nephritis in MRL/lpr mice.
Asunto(s)
Enfermedades Autoinmunes/prevención & control , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/fisiología , Nefritis/prevención & control , Animales , Anticuerpos Antinucleares/sangre , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Femenino , Inmunoglobulina G/sangre , Inductores de Interferón/efectos adversos , Interferón-alfa/sangre , Riñón/patología , Ligandos , Pulmón/patología , Ratones , Ratones Endogámicos MRL lpr , Ratones Noqueados , Nefritis/genética , Nefritis/inmunología , Poli I-C/efectos adversos , Glándulas Salivales/patología , Receptor Toll-Like 3/fisiologíaRESUMEN
Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease that is characterized by the production of multiple autoantibodies and immune complex formation. Lupus nephritis, which has various histological patterns and variable clinical outcomes, is one of the most important complications of SLE. Although this pathogenetic mechanism in each histologically different type of nephritis remains unclear, recent findings in murine lupus elucidate an essential role for the Th1 cytokine in the development of diffuse lupus nephritis (DLN), and Th2 cytokine in that of membranous lupus nephritis (MLN). These data support the hypothesis that individual Th1/Th2 balance is one of the critical determinants for histopathology of lupus nephritis. Therefore the value of Th1/Th2 ratio of the peripheral CD4+ T cells in SLE patients could be a useful index to predict histopathology of lupus nephritis.
Asunto(s)
Lupus Eritematoso Sistémico/inmunología , Nefritis Lúpica/inmunología , Células TH1/fisiología , Células Th2/fisiología , Animales , Citocinas/análisis , Humanos , RatonesRESUMEN
OBJECTIVE: To examine whether the platelet-derived growth factor (PDGF) receptor antagonist imatinib ameliorates glomerulonephritis in MRL/lpr mice, a condition that is similar to severe lupus nephritis in humans. METHODS: Sixteen-week-old MRL/lpr female mice having an advanced stage of glomerulonephritis were divided into 3 groups according to treatment: 1) 50 mg/kg or 2) 10 mg/kg of imatinib (administered orally 4 times a week up to 24 weeks of age) or 3) vehicle solution (untreated group). The histopathologic condition of the kidneys and salivary glands of each mouse as well as the cumulative survival rates, extent of lymphadenopathy and splenomegaly, and serum chemistry and immunologic values were assessed. RESULTS: In mice treated with 50 mg/kg imatinib, neither proliferation of glomerular cells nor crescent formation occurred. A drastic decrease in mesangial matrix was noted. Mice treated with 50 mg/kg imatinib had a prolonged life span compared with mice treated with 10 mg/kg imatinib and untreated mice. Expression of PDGF receptor and transforming growth factor beta messenger RNA in the kidneys was significantly reduced in the 50 mg/kg imatinib-treated mice compared with that in the 10 mg/kg imatinib-treated mice (P < 0.05) and the untreated mice (P < 0.01). Intriguingly, lymphadenopathy and salivary gland inflammation were also attenuated in imatinib-treated mice, in a dose-dependent manner. Serum levels of IgG and anti-double-stranded DNA antibodies were also reduced in the imatinib-treated mice. CONCLUSION: These findings indicate that imatinib has a pleiotropic therapeutic effect, namely, the inhibition of PDGF signaling and immunosuppression, on the glomerulonephritis of MRL/lpr mice, which suggests a potential application of this drug in the treatment of human lupus nephritis.
Asunto(s)
Antineoplásicos/farmacología , Nefritis Lúpica/tratamiento farmacológico , Nefritis Lúpica/inmunología , Piperazinas/farmacología , Pirimidinas/farmacología , Animales , Autoanticuerpos/sangre , Benzamidas , Nitrógeno de la Urea Sanguínea , Linfocitos T CD4-Positivos/inmunología , Creatinina/sangre , ADN/inmunología , Femenino , Glomerulonefritis/tratamiento farmacológico , Glomerulonefritis/inmunología , Glomerulonefritis/mortalidad , Mesilato de Imatinib , Inmunoglobulina G/sangre , Interferón gamma/genética , Nefritis Lúpica/mortalidad , Enfermedades Linfáticas/tratamiento farmacológico , Enfermedades Linfáticas/inmunología , Enfermedades Linfáticas/mortalidad , Ratones , Ratones Endogámicos MRL lpr , Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Proteinuria/tratamiento farmacológico , Proteinuria/inmunología , Proteinuria/mortalidad , Glándulas Salivales/inmunología , Índice de Severidad de la Enfermedad , Bazo/inmunología , Bazo/patología , Esplenomegalia/tratamiento farmacológico , Esplenomegalia/inmunología , Esplenomegalia/mortalidad , Análisis de SupervivenciaRESUMEN
MRL/lpr mice develop spontaneous glomerulonephritis that is essentially identical with diffuse proliferative glomerulonephritis (World Health Organization class IV) in human lupus nephritis. Lupus nephritis is one of the most serious complications of systemic lupus erythematosus. Diffuse proliferative glomerulonephritis is associated with autoimmune responses dominated by Th1 cells producing high levels of IFN-gamma. The initial mounting of Th1 responses depends on the function of the WSX-1 gene, which encodes a subunit of the IL-27R with homology to IL-12R. In mice deficient for the WSX-1 gene, proper Th1 differentiation was impaired and abnormal Th2 skewing was observed during infection with some intracellular pathogens. Disruption of the WSX-1 gene dramatically changed the pathophysiology of glomerulonephritis developing in MRL/lpr mice. WSX-1-/- MRL/lpr mice developed disease resembling human membranous glomerulonephritis (World Health Organization class V) with a predominance of IgG1 in glomerular deposits, accompanied by increased IgG1 and IgE in the sera. T cells in WSX-1-/- MRL/lpr mice displayed significantly reduced IFN-gamma production along with elevated IL-4 expression. Loss of WSX-1 thus favors Th2-type autoimmune responses, suggesting that the Th1/Th2 balance may be a pivotal determinant of human lupus nephritis development.
Asunto(s)
Modelos Animales de Enfermedad , Glomerulonefritis Membranosa/inmunología , Ratones Endogámicos MRL lpr/inmunología , Receptores de Citocinas/deficiencia , Células Th2/inmunología , Animales , Ensayo de Inmunoadsorción Enzimática , Femenino , Glomerulonefritis Membranosa/genética , Glomerulonefritis Membranosa/patología , Inmunoglobulina E/análisis , Inmunoglobulina G/análisis , Inmunohistoquímica , Interferón gamma/inmunología , Interleucina-4/inmunología , Nefritis Lúpica/genética , Nefritis Lúpica/inmunología , Nefritis Lúpica/patología , Ratones , Ratones Endogámicos MRL lpr/genética , Ratones Mutantes , Microscopía Electrónica de Transmisión , Receptores de Citocinas/genética , Receptores de Interleucina , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células TH1/inmunologíaRESUMEN
We encountered two patients of recurrent nephrotic syndrome (NS) after renal transplantation that was resistant to plasma exchange (PEX). Case 1 was a 34-year-old man with a living-related renal transplant for type-I membranoproliferative glomerulonephritis (MPGN) related end-stage renal disease (ESRD). He developed overt proteinuria 7 months post-transplant and presented with NS 5 months later. Biopsy of the transplant kidney revealed recurrent type I MPGN, but no features of acute rejection (AR) or chronic allograft nephropathy (CAN). He was treated with cyclophosphamide (CP), oral prednisolone (40 mg/d), an anti-platelet agent, heparin sulfate, and PEX, but the nephrotic state persisted and renal function was deteriorated. He recommenced hemodialysis 3 yr and 9 months after renal transplant. Case 2 was a 47-year-old male who underwent living-related renal transplant for ESRD due to focal segmental glomerulosclerosis (FSGS). He presented with proteinuria shortly after renal transplantation. He also had frequent episodes of AR. Graft biopsy revealed recurrent FSGS. Treatment of pulse methylprednisolone and PEX was transiently effective, but NS relapsed shortly after PEX. Graft biopsy at our hospital showed features of CAN with moderate interstitial fibrosis and tubular atrophy, presence of intraglomerular foam cells but no segmental sclerosis. Treatment with 12 courses of low-density lipoprotein apheresis (LDL-A) reduced proteinuria from 9.6 to 2.0 g/d, and incomplete remission has been maintained for more than 1 yr after LDL-A with slowly progressive renal dysfunction. Despite recent therapeutic advances, including the use of immunosuppressants and PEX, treatment of recurrent disease remains difficult. The LDL-A might be useful in cases with recurrent FSGS resistant to PEX.