RESUMEN
BACKGROUND: Evidence increasingly points to the importance of chronic hypoxia in the tubulointerstitium as a final common pathway to end-stage renal disease (ESRD). Beraprost sodium (BPS) is an orally active prostacyclin (PGI2) analogue demonstrating prevention of the progression of chronic kidney disease (CKD) in various animal models by maintaining renal blood flow and attenuating renal ischemic condition. METHODS: This multicenter, randomized, double-blind, placebo-controlled, phase II trial was designed to determine the recommended dose of the sustained-release form of BPS (TRK-100STP 120 µg/day or 240 µg/day) in Japanese patients with CKD. TRK-100STP was administered to a total of 112 patients. The primary efficacy endpoint was the difference in the slope of the regression line of reciprocal of serum creatinine (1/SCr) over time, obtained by the least-squares method. RESULTS: Regarding the primary endpoint, statistical superiority of TRK-100STP 240 µg over placebo was not confirmed and so a recommended dose was not determined. Compared to placebo, however, the slope of regression line of 1/SCr, elevation of SCr and serum cystatin C during the treatment period revealed greater improvement at 120 µg, at both doses, and at 240 µg, respectively. In terms of safety, both TRK-100STP treatment groups were well tolerated. CONCLUSIONS: Although the study failed to meet the primary endpoint, results indicate that TRK-100STP may potentially prevent the decline in renal function of CKD patients independent of blood pressure or urinary protein levels. TRIAL REGISTRATION: NCT02480751. June 21, 2015.
Asunto(s)
Creatinina/sangre , Epoprostenol/análogos & derivados , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/fisiopatología , Vasodilatadores/administración & dosificación , Administración Oral , Adulto , Anciano , Creatinina/orina , Cistatina C/sangre , Preparaciones de Acción Retardada , Progresión de la Enfermedad , Método Doble Ciego , Epoprostenol/administración & dosificación , Epoprostenol/efectos adversos , Femenino , Tasa de Filtración Glomerular , Humanos , Masculino , Persona de Mediana Edad , Vasodilatadores/efectos adversosRESUMEN
We have previously demonstrated that renoprotective effects of a prostacyclin analog, beraprost sodium, on the kidney of anti-glomerular basement membrane glomerulonephritis (GN) rats. The aim of this study is to address the renoprotection mechanism of beraprost sodium, especially in the terminal stage of GN. Beraprost sodium was orally administrated from 2 to 7 weeks after induction of GN, and renal function, morphology, protein and mRNA levels were analyzed. We found the beraprost sodium treatment suppressed the structural regression of renal microvascular network and decline of renal blood flow occurred in the kidney of GN rats. To address the mechanism of the structural maintenance, we focused on apoptosis because the increased number of apoptotic renal microvascular endothelial cells and tubular epithelial cells was observed in the kidneys of GN rats as compared with normal and beraprost sodium treated rats. Protein and mRNA analyses demonstrated that mitochondria-dependent apoptotic pathway was activated in the kidneys of GN rats, and beraprost sodium suppressed the activation by modulating the expression patterns of pro- and anti-apoptotic factors. These results suggest that inhibition of mitochondria-dependent apoptosis of renal cells in GN kidney and consequent maintenance of renal functional structures, including microvascular network might contribute to the renoprotective effect of beraprost sodium in GN.
Asunto(s)
Apoptosis/efectos de los fármacos , Epoprostenol/análogos & derivados , Glomerulonefritis/tratamiento farmacológico , Riñón/irrigación sanguínea , Microvasos/efectos de los fármacos , Mitocondrias/fisiología , Animales , Capilares , Caspasas/análisis , Modelos Animales de Enfermedad , Epoprostenol/uso terapéutico , Membrana Basal Glomerular/inmunología , Glomerulonefritis/etiología , Glomerulonefritis/fisiopatología , Sueros Inmunes/administración & dosificación , Proteínas Inhibidoras de la Apoptosis/genética , Riñón/química , Riñón/patología , Masculino , Microscopía Electrónica de Rastreo , Microvasos/patología , Proteínas Proto-Oncogénicas c-bcl-2/genética , ARN Mensajero/análisis , Ratas , Ratas Endogámicas WKY , Proteína X Asociada a bcl-2/genéticaRESUMEN
BACKGROUND: Chronic kidney disease (CKD) is public health concern even in Asian countries. TRK-100STP, a sustained release tablet of an orally-active prostacyclin analogue, beraprost sodium, is suggested to suppress worsening of some parameters of renal filtration function, containing in slope of 1/serum creatinine (1/SCr) vs. time in a phase II clinical trial. METHODS/DESIGN: We describe the design of the phase IIb/III trial of TRK-100STP, CASSIOPEIR (CRF Asian Study with Oral PGI2 derivative for Evaluating Improvement of Renal function) conducted in approximately 160 centers in China, Hong Kong, Japan, Malaysia, Republic of Korea, Taiwan, and Thailand. A total of 750 patients (n = 250 per group) with primary glomerular disease or nephrosclerosis were planned to be enrolled. Patients were randomized into one of three treatment groups in a double-bind, placebo-controlled manner: TRK-100STP 60 µg b.i.d.; TRK-100STP 120 µg b.i.d.; or placebo. The treatment period is planned to last 2 to 4 years. The primary efficacy endpoint is the renal composite endpoint including doubling of SCr and ESRD (dialysis induction, renal transplantation, or increase in SCr to ≥ 6.0 mg/dL). DISCUSSION: This trial targeting CKD patients is designed to (a) demonstrate the superiority of TRK-100STP over placebo using renal composite endpoints, (b) determine the recommended clinical dose, and (c) assess the safety of TRK-100STP in this population and setting. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01090037.
Asunto(s)
Epoprostenol/análogos & derivados , Epoprostenol/administración & dosificación , Glomérulos Renales/efectos de los fármacos , Nefroesclerosis/tratamiento farmacológico , Nefroesclerosis/epidemiología , Administración Oral , Adulto , Anciano , Método Doble Ciego , Epoprostenol/química , Femenino , Estudios de Seguimiento , Humanos , Internacionalidad , Glomérulos Renales/patología , Masculino , Persona de Mediana Edad , Nefroesclerosis/diagnóstico , Adulto JovenRESUMEN
We conducted a multicenter, randomized, double-blind, placebo-controlled, phase IIb/III study (CASSIOPEIR) using a renal composite endpoint (i.e., doubling of SCr or end-stage renal disease) in seven Asian countries/region. CASSIOPEIR compared TRK-100STP (120 µg and 240 µg) with placebo in patients with non-diabetic CKD patients with primary glomerular disease or nephrosclerosis (n = 892). However, the superiority of TRK-100STP over placebo was not observed. A prior phase II study on which the Phase IIb/III study design was based included only Japanese patients. We therefore evaluated TRK-100STP efficacy and safety in a subgroup of Japanese patients using the CASSIOPEIR dataset. As the timing of treatment initiation is important in CKD, we conducted additional subgroup analyses based on the baseline serum creatinine (SCr) and eGFR. ITT analysis was performed in a Japanese subgroup (n = 339) in which the primary endpoint was the first occurrence of renal composite endpoint. Significant differences were observed for TRK-100STP 240 µg vs. placebo (P = 0.0493; HR 0.69 [95% CI: 0.47, 1.00]), but no significant difference was observed between TRK-100 120 µg and placebo (P = 0.3523; HR 0.85). More prominent improvement was observed with TRK-100STP 240 µg vs. placebo for baseline SCr < 3.0 mg/dL (P = 0.0031; HR 0.43); SCr < 3.5 mg/dL (P = 0.0237, HR 0.59); and eGFR ≥ 10 mL/min/1.73 m2 (P = 0.0339, HR0.67), respectively. No significant changes in urinary albumin/creatinine ratio and blood pressure were observed. TRK-100STP was generally well tolerated and most adverse drug reactions were mild or moderate in severity. In conclusion, in the Japanese subgroup of CASSIOPEIR, TRK-100STP 240 µg/day significantly improved the renal composite endpoint compared with placebo, with greater efficacy in subjects with SCr < 3.5 or eGFR ≥ 10 mL/min/1.73 m2 .
Asunto(s)
Epoprostenol/análogos & derivados , Nefroesclerosis/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Insuficiencia Renal Crónica/tratamiento farmacológico , Método Doble Ciego , Epoprostenol/uso terapéutico , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
BACKGROUND AND OBJECTIVES: Beraprost sodium (BPS), an orally administrable prostaglandin I2 derivative, is used for the treatment of chronic arterial occlusion and pulmonary arterial hypertension and has potential efficacy in nephropathy. Beraprost sustained release (beraprost SR) is an oral sustained-release formulation of BPS. To confirm the dose rationale reported in a multi-regional study of nephropathy patients in Asia, this open-label study evaluated ethnic differences in the pharmacokinetic profiles of BPS and its active diastereomer (BPS-314d) after beraprost SR administration among healthy Japanese, Chinese, and Korean adult males. METHODS: Twelve healthy subjects in each ethnic group were enrolled. Subjects received a single oral dose of 120 µg beraprost SR under fasting conditions. RESULTS: The geometric mean ratio (90% confidence interval) of the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration (AUClast) of BPS was 1.12 (0.85-1.48) and 1.40 (1.05-1.86) in Chinese, and 1.18 (0.90-1.55) and 1.18 (0.89-1.58) in Korean compared to Japanese subjects. These differences were not clinically relevant. Similarly, differences in the Cmax and AUClast of BPS-314d were also small among the ethnic groups. Urinary excretion of BPS and BPS-314d was limited in all ethnic groups. Together, these findings indicate that the pharmacokinetics of beraprost SR are not affected by ethnic background. CONCLUSIONS: There were no clinically meaningful ethnic differences in the pharmacokinetics of BPS and BPS-314d following beraprost SR administration among Japanese, Chinese and Korean populations.
Asunto(s)
Epoprostenol/análogos & derivados , Administración Oral , Adulto , Pueblo Asiatico , China , Preparaciones de Acción Retardada , Epoprostenol/farmacocinética , Ayuno , Humanos , Japón , Masculino , República de Corea , Adulto JovenRESUMEN
TRK-100STP, a sustained-release preparation of the orally active prostacyclin analogue beraprost sodium, targets renal hypoxia. This study aimed to show the superiority of TRK-100STP over placebos in patients with chronic kidney disease (with either primary glomerular disease or nephrosclerosis) to determine the recommended dose. CASSIOPEIR (Chronic Renal Failure Asian Study with Oral PGI2 Derivative for Evaluating Improvement of Renal Function) was a randomized, double-blind, placebo-controlled study conducted at 160 sites in seven Asia-Pacific countries and regions. Eligible patients (n = 892) were randomized to TRK-100STP 120, 240 µg, or placebo for a treatment period of up to 4 years. The primary efficacy endpoint was time to first occurrence of a renal composite: doubling of serum creatinine or occurrence of end-stage renal disease. No significant differences were observed in composite endpoints between TRK-100STP and placebo (P = 0.5674). Hazard ratios (95% CI) in the TRK-100STP 120 and 240 µg vs. placebo groups were 0.98 (0.78, 1.22) and 0.91 (0.72, 1.14), respectively. The overall incidence of adverse events and adverse drug reactions was comparable between treatment arms.
Asunto(s)
Epoprostenol/análogos & derivados , Nefroesclerosis/tratamiento farmacológico , Insuficiencia Renal Crónica/tratamiento farmacológico , Vasodilatadores/administración & dosificación , Adulto , Anciano , Creatinina/sangre , Preparaciones de Acción Retardada , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Epoprostenol/administración & dosificación , Epoprostenol/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nefroesclerosis/fisiopatología , Insuficiencia Renal Crónica/fisiopatología , Vasodilatadores/efectos adversos , Adulto JovenRESUMEN
The purpose of the present study was to evaluate the pharmacokinetics of beraprost sodium (BPS) and its active enantiomer, BPS-314d, in Japanese subjects with impaired kidney function. The plasma and urine concentrations of BPS and BPS-314d were measured following the single oral administration of 120 µg of BPS as the sustained-release tablet, TRK-100STP, under fasting conditions to 18 subjects with impaired kidney function (stage 2, 3, and 4 chronic kidney disease [CKD] as categorized by the estimated glomerular filtration rate) and to 6 age-, body weight-, and gender-matched subjects with normal kidney function (stage 1 CKD). The Cmax values (mean ± SD) of BPS in stage 1, 2, 3, and 4 CKD, respectively, were 84.9 ± 22.9, 119.8 ± 36.4, 190.6 ± 137.3, and 240.2 ± 110.5 pg/mL; its AUC0-48h were 978 ± 226, 1252 ± 427, 1862 ± 964, and 1766 ± 806 pg·h/mL, respectively, and its cumulative urinary excretion rates were 0.704 ± 0.351%, 0.638 ± 0.292%, 0.485 ± 0.294%, and 0.159 ± 0.136%. The Cmax values of BPS-314d were 22.4 ± 6.4, 30.8 ± 8.5, 46.7 ± 30.6, and 54.4 ± 25.2 pg/mL, its AUC0-48h were 155 ± 56, 226 ± 67, 341 ± 176, and 329 ± 143 pg·h/mL, and its cumulative urinary excretion rates were 0.428 ± 0.242%, 0.349 ± 0.179%, 0.356 ± 0.270%, and 0.096 ± 0.099%, respectively. Adverse events were reported in 2 subjects with stage 2 CKD and 1 subject with stage 4 CKD. The Cmax and AUC0-48h of BPS and BPS-314d were higher based on the severity of impaired kidney function. No relationship was observed between the incidence of adverse events and the severity, and tolerability was confirmed. We consider that dose adjustment is not necessary, but BPS is more carefully treated in patients with impaired kidney function.
Asunto(s)
Epoprostenol/análogos & derivados , Insuficiencia Renal/sangre , Insuficiencia Renal/orina , Administración Oral , Anciano , Preparaciones de Acción Retardada , Epoprostenol/administración & dosificación , Epoprostenol/farmacocinética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/farmacocinética , Unión Proteica/fisiología , Insuficiencia Renal/tratamiento farmacológicoRESUMEN
In rats receiving bilateral femoral arteries ligation (day 0), repeated oral administration of the prostacyclin derivative beraprost sodium (50 microg/kg, b.i.d.) from day 1 to day 5 resulted in a significant prolongation in walking time in rotarod walking exercise performed on day 5. Similarly, results were obtained in rats with bilateral femoral arterial thrombosis induced by application of FeCl(3)/HCl. In the ligation model, a significant increase was observed in femoral/carotid arterial blood pressure ratio even on day 2. These results indicated that beraprost sodium improves blood flow and walking disturbances associated with arterial occlusion in rats.
Asunto(s)
Epoprostenol/análogos & derivados , Claudicación Intermitente/tratamiento farmacológico , Animales , Arteriopatías Oclusivas/tratamiento farmacológico , Epoprostenol/uso terapéutico , Arteria Femoral , Masculino , Ratas , Ratas Wistar , Flujo Sanguíneo Regional/efectos de los fármacos , CaminataRESUMEN
Effects of beraprost sodium, a chemically stable prostacyclin analogue, on renal dysfunction in an experimental rat model of glomerulonephritis were investigated. Beraprost sodium (30, 100 and 300 microg/kg) was orally given twice daily from the late stage of nephritis in which renal dysfunction was already developed. Beraprost sodium treatment inhibited the increase in urinary protein, serum creatinine and blood urea nitrogen, and the decrease in creatinine clearance. The elevation of serum creatinine was also inhibited by predonisolone (1 mg/kg). However, captopril (25, 50 and 100 mg/kg) and dipyridamole (20 and 60 mg/kg) failed to inhibit the elevation of serum creatinine. In the beraprost sodium-treated nephritic rats, the increase in mRNA levels for monocyte chemoattractant protein-1 (MCP-1) and collagen in the kidney was inhibited. These results suggest that beraprost sodium ameliorates developed renal dysfunction and is possibly an effective agent for the treatment of human glomerulonephritis.
Asunto(s)
Epoprostenol/análogos & derivados , Epoprostenol/uso terapéutico , Glomerulonefritis/tratamiento farmacológico , Riñón/fisiopatología , Inhibidores de Agregación Plaquetaria/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Animales , Antiinflamatorios/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Nitrógeno de la Urea Sanguínea , Peso Corporal/efectos de los fármacos , Captopril/uso terapéutico , Quimiocina CCL2/biosíntesis , Quimiocina CCL2/metabolismo , Creatinina/orina , Dipiridamol/uso terapéutico , Glomerulonefritis/fisiopatología , Riñón/efectos de los fármacos , Riñón/metabolismo , Pruebas de Función Renal , Glomérulos Renales/inmunología , Masculino , Prednisolona/uso terapéutico , Proteinuria/inducido químicamente , ARN Mensajero/biosíntesis , Conejos , Ratas , Ratas Endogámicas WKY , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Beraprost sodium, a stable prostacyclin analog, was showed to improve survival rates in two different rat models, anti-glomerular basement membrane (GBM) glomerulonephritis (GN) and 5/6 nephrectomized (Nx) chronic kidney disease (CKD) rats. In the anti-GBM rat, beraprost sodium (0.2 and 0.6 mg/kg/day) improved survival rate (hazard ratio for beraprost sodium 0.6 mg/kg/day group, 0.10; 95% confidence interval, 0.01 to 0.68). Subsequently, in the 5/6 Nx CKD rat, beraprost sodium (0.6 mg/kg/day) improved survival rate (hazard ratio for beraprost sodium, 0.46; 95% confidence interval, 0.23 to 0.92), serum creatinine doubling time and the slope of the reciprocal of serum creatinine. In the anti-GBM GN rats, beraprost sodium suppressed the serum accumulation of representative uremic toxins such as indoxyl sulfate. Furthermore, beraprost sodium inhibited human aortic endothelial cell (HAEC) injury induced by indoxyl sulfate, indicating that beraprost sodium might have a protective effect against cardiovascular damage due to CKD. These results show that beraprost sodium can improve the survival rates in two rat models of anti-GBM GN and 5/6 Nx CKD rats by protecting endothelial cells and thereby ameliorating decreased renal function. Therefore, clinical studies are needed in patients with chronic kidney failure to determine whether beraprost sodium will become a useful medication in CKD.
Asunto(s)
Epoprostenol/análogos & derivados , Membrana Basal Glomerular/efectos de los fármacos , Glomerulonefritis/tratamiento farmacológico , Nefrectomía , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/cirugía , Animales , Aorta/citología , AMP Cíclico/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Epoprostenol/farmacología , Epoprostenol/uso terapéutico , Glomerulonefritis/sangre , Humanos , Indicán/sangre , Masculino , Ratas , Insuficiencia Renal Crónica/sangre , Análisis de SupervivenciaRESUMEN
OBJECTIVE: The prostacyclin analog, beraprost sodium (BPS), was examined for its potential to improve the symptoms of obesity-type diabetes (i.e., hyperglycemia, hyperinsulinemia, dyslipidemia, histopathologic changes, and diabetic complications). RESEARCH DESIGN AND METHODS: Obese Zucker rats, an experimental model of genetic obesity-induced type 2 diabetes, were repeatedly administered BPS at oral doses of 0.2 or 0.6 mg x kg(-1) x day(-1) b.i.d. for 12 weeks, and serum chemistry, urinalysis, and histopathologic examination were performed. RESULTS: BPS dose-dependently suppressed serum glucose, insulin, triglyceride, and cholesterol levels in obese animals. In oral glucose tolerance test, BPS suppressed the post-glucose-loading elevation of serum glucose in a dose-dependent manner. Urinary N-acetyl-beta-D-glucosaminidase was significantly lower in BPS-treated obese animals compared with control animals, although no significant differences were observed in urinary protein levels between the BPS-treated groups and the control group. In addition, histopathologic examination revealed significant protective effects of BPS against renal disorder in obese animals. Histopathologically, BPS also inhibited the progression of hepatic steatosis, hypertrophy of adipose tissue, and pancreatic fibrosis. Furthermore, thermographic analysis of the hind limb sole skin surface indicated a significant increase in temperature in BPS-treated animals, compared with control animals, which was likely due to improved blood circulation by administration of BPS. CONCLUSIONS: BPS suppressed the pathogenesis and development of diabetes and its complication, nephropathy, which was presumably accompanied by improving glucose intolerance and insulin resistance in obese Zucker rats.
Asunto(s)
Crioprotectores/uso terapéutico , Epoprostenol/análogos & derivados , Síndrome Metabólico/prevención & control , Obesidad/complicaciones , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/patología , Animales , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Colesterol/sangre , Epoprostenol/uso terapéutico , Hemoglobina Glucada/efectos de los fármacos , Hemoglobina Glucada/metabolismo , Insulina/sangre , Riñón/efectos de los fármacos , Riñón/patología , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Síndrome Metabólico/tratamiento farmacológico , Síndrome Metabólico/metabolismo , Síndrome Metabólico/patología , Páncreas/efectos de los fármacos , Páncreas/patología , Ratas , Ratas Zucker , Temperatura Cutánea/efectos de los fármacos , Triglicéridos/sangreRESUMEN
Unilateral ureteral obstruction (UUO) is a representative model for investigating the common mechanism of decreasing renal function in chronic renal failure. In this study, we present a new partial UUO model in adult rats and evaluated the effect of beraprost sodium (BPS: stable prostaglandin I(2) (PGI(2)) analog). We could make reproductive and uniform partial UUO by ligating the left ureter together with a 0.5 mm diameter stainless steel wire with nylon thread, and withdrawing the stainless wire. One week later, the ureteral obstruction was released. After 3 weeks from the release of UUO, all animals of control group, without BPS administration, developed basophilic degeneration of tubular epithelium, tubular dilatation and interstitial fibrosis. The areas of tubular degeneration and fibrosis were significantly reduced in the BPS group, orally administered BPS 300 microg/kg twice a day from the next day of the release of obstruction, than in control group. In conclusion, we can established the adult rat partial UUO-release model and revealed that BPS can inhibit renal tubular damage and tubulointerstitial fibrosis.
Asunto(s)
Modelos Animales de Enfermedad , Epoprostenol/análogos & derivados , Fallo Renal Crónico/tratamiento farmacológico , Túbulos Renales/efectos de los fármacos , Obstrucción Ureteral/complicaciones , Animales , Epoprostenol/farmacología , Epoprostenol/uso terapéutico , Fibrosis , Fallo Renal Crónico/etiología , Fallo Renal Crónico/patología , Túbulos Renales/patología , Masculino , Ratas , Ratas Wistar , Obstrucción Ureteral/patologíaAsunto(s)
Epoprostenol/análogos & derivados , Hipertensión Pulmonar/tratamiento farmacológico , Vasodilatadores/administración & dosificación , Vasodilatadores/farmacología , Animales , Preparaciones de Acción Retardada , Epoprostenol/administración & dosificación , Epoprostenol/farmacología , Humanos , RatasRESUMEN
BACKGROUND/AIM: Prolonged exposure to hyperglycemia is one of the key factors to induce progressive diabetic nephropathy in humans. We examined whether or not the same phenomenon is observed in a nonobese type 2 diabetes model, in Goto-Kakizaki (GK) rats. METHODS: Urine and serum samples from GK and Wistar rats were collected to measure biochemical parameters of the renal function. The kidneys of these animals were histopathologically and immunohistochemically analyzed. RESULTS: Moderate hyperglycemia was sustained in GK rats during the experimental period. Noticeable morphological changes in the kidneys such as segmental glomerulosclerosis and tubulointerstitial fibrosis were observed only at 24 months of age. The expression of alpha smooth muscle actin and type IV collagen in glomeruli and tubulointerstitium was increased at 12 months of age and later. The macrophage infiltration was increased in parallel with the progression of renal lesions. The excretion of urinary protein in GK rats was increased only at 24 months of age. Moreover, the functional and morphological changes in Wistar rats were less severe than in age-matched GK rats. CONCLUSIONS: We conclude that renal changes of GK rats at a late stage were similar to those of progressive human diabetic nephropathy and that prolonged hyperglycemia may play a more crucial role in inducing progressive diabetic nephropathy than aging and obesity.