AIMTo investigate the therapeutic potential of tesevatinib （TSV）, a unique multi-kinase inhibitor currently in Phase Ⅱ clinical trials for autosomal dominant polycystic kidney disease （ADPKD）, in well-defined rod...AIMTo investigate the therapeutic potential of tesevatinib （TSV）, a unique multi-kinase inhibitor currently in Phase Ⅱ clinical trials for autosomal dominant polycystic kidney disease （ADPKD）, in well-defined rodent models of autosomal recessive polycystic kidney disease （ARPKD）. METHODSWe administered TSV in daily doses of 7.5 and 15 mg/kg per day by I.P. to the well characterized bpk model of polycystic kidney disease starting at postnatal day（PN） 4 through PN21 to assess efficacy and toxicity in neonatal mice during postnatal development and still undergoing renal maturation. We administered TSV by oral gavage in the same doses to the orthologous PCK model （from PN30 to PN90） to assess effcacy and toxicity in animals where developmental processes are complete. The following parameters were assessed： Body weight, total kidney weight; kidney weight to body weight ratios; and morphometric determination of a cystic index and a measure of hepatic disease. Renal function was assessed by： Serum BUN; creatinine; and a 12 h urinary concentrating ability. Validation of reported targets including the level of angiogenesis and inhibition of angiogenesis （active VEGFR2/KDR） was assessed by Western analysis.RESULTSThis study demonstrates that： （1） in vivo pharmacological inhibition of multiple kinase cascades with TSV reduced phosphorylation of key mediators of cystogenesis： EGFR, ErbB2, c-Src and KDR; and （2） this reduction of kinase activity resulted in signifcant reduction of renal and biliary disease in both bpk and PCK models of ARPKD. The amelioration of disease by TSV was not associated with any apparent toxicity.CONCLUSIONThe data supports the hypothesis that this multi-kinase inhibitor TSV may provide an effective clinical therapy for human ARPKD.展开更多
Background Autosomal recessive polycystic kidney disease （ARPKD） is a rare inherited disease, which is a disorder with multiple organ involvement, mainly the kidney and liver. It is caused by mutations in the PKHD1 ...Background Autosomal recessive polycystic kidney disease （ARPKD） is a rare inherited disease, which is a disorder with multiple organ involvement, mainly the kidney and liver. It is caused by mutations in the PKHD1 gene. Here, we reported the clinical characteristics of a case with ARPKD and analyze the genetic features of this patient as well as of his father using targeted exome sequencing and Sanger sequencing. Methods Genomic DNA was extracted from peripheral blood leukocytes obtained from a patient with ARPKD. The mutations were identified using exome sequencing and confirmed by Sanger sequencing. Results The patient was diagnosed as ARPKD based on ultrasonography and abdominal computed tomography which showed polycystic changes, multiple calcinosis of both kidneys, and multiple dilated bile ducts of the liver. Compound heterozygous PKHD1 gene mutations A979G and G5935A, which lead to substitution of an asparagine for an aspartate at amino acid 327 （N327D） and a glycine for an arginine at amino acid 1979 （G1979R） respectively, were identified using targeted exome sequencing and confirmed by Sanger sequencing for the patient. In addition, the father of the patient was identified to be a carrier of heterozygous A979G mutation of this gene. Conclusions We identified that the compound heterozygous PKHD1 gene mutations are the molecular basis of the patient with ARPKD. Targeted exome sequencing is suitable for genetic diagnosis of single-gene inherited diseases like ARPKD in which the pathogenic gene is a large.展开更多
PKHD1 mutations are generally considered to cause autosomal recessive polycystic kidney disease(ARPKD).ARPKD is a rare disorder and one o f the most severe conditions leading to end-stage renal disease in childhood.Wi...PKHD1 mutations are generally considered to cause autosomal recessive polycystic kidney disease(ARPKD).ARPKD is a rare disorder and one o f the most severe conditions leading to end-stage renal disease in childhood.With the biallelic deletion mutation,patients have difficulty in surviving the perinatal period,resulting in perinatal or neonatal death.This study retrospectively analyzed patient characteristics,imaging characteristics,laboratory examinations and family surveys from 7 Chinese children with different PKHD1 gene mutations diagnosed by high-throughput sequencing from January 2014 to February 2018.O f the 7 children,there were 3 males and 4 females.Eight missense mutations,two frameshift mutations,two deletion mutations,and two intronic slicing mutations were identified.Six of the mutations have not previously been identified.In the literature search,we identified a total of 29 Chinese children with PKHD1 mutations.The missense mutation c.2507T>C in exon 24 was found in one patient in our study,and five patients with liver fibrosis but normal renal function were reported in the literature.The missense mutation c.5935G>A in exon 37 was found in two patients in our study and three cases in the literature.Four patients had renal failure at an age as young as 1 year of those five patients with the missense mutation c.5935G>A in exon 37.It was concluded that:(1)Kidney length more than 2-3 SDs above the mean and early-onset hypertension might be associated with PKHDI-associated ARPICD;(2)The more enlarged the kidney size is,the lower the renal function is likely to be;(3)c.5935G>A may be a hot spot that leads to early renal failure in Chinese children with PKHD1 mutations;(4)c.2507T>C may be a hot-spot mutation associated with hepatic lesions in Chinese children with PKHD1.展开更多
Combined liver-kidney transplantation(CLKT)is a rarely performed complex surgical procedure in children and involves transplantation of kidney and either whole or part of liver donated by the same individual(usually a...Combined liver-kidney transplantation(CLKT)is a rarely performed complex surgical procedure in children and involves transplantation of kidney and either whole or part of liver donated by the same individual(usually a cadaver)to the same recipient during a single surgical procedure.Most common indications for CLKT in children are autosomal recessive polycystic kidney disease and primary hyperoxaluria type 1.Atypical haemolytic uremic syndrome,methylmalonic academia,and conditions where liver and renal failure co-exists may be indications for CLKT.CLKT is often preferred over sequential liver-kidney transplantation due to immunoprotective effects of transplanted liver on renal allograft;however,liver survival has no significant impact.Since CLKT is a major surgical procedure which involves multiple and complex anastomosis surgeries,acute complications are not uncommon.Bleeding,thrombosis,haemodynamic instability,infections,acute cellular rejections,renal and liver dysfunction are acute complications.The long-term outlook is promising with over 80%5-year survival rates among those children who survive the initial six-month postoperative period.展开更多
Background: Methylmalonic aciduria (MMA) is a genetic disorder of aminoacid metabolism, due to mutations in methylmalonyl-CoA mutase, which leads to the accumulation of methylmalonic acid in body fluids. Patients typi...Background: Methylmalonic aciduria (MMA) is a genetic disorder of aminoacid metabolism, due to mutations in methylmalonyl-CoA mutase, which leads to the accumulation of methylmalonic acid in body fluids. Patients typically present at the age of 1 month to 1 year with dehydration, renal impairment as well as neurologic manifestations viz. seizure, encephalopathy, strokes and disease in the globus pallidi. The case: a 26-year-old man presented with severe acute on top of chronic renal disease with serum creatinine at 590 umol/L and bilateral 8 cm kidneys with thin and echogenic cortex. He had: (a) hypernatremic dehydration, metabolic acidosis and high ammonia level with (b) a history of multiple similar attacks since the age of 8 months. Diagnosis of MMA was confirmed by high serum and urine enzymatic levels as well as genetic testing. His initial management included support with replacements of fluids, electrolytes, and bicarbonates as well as intravenous dextrose, vitamin B12 and broad-spectrum antibiotic (Meropenem) for his chest infection. Subsequently, he received 1) CARBAGLU (carglumic acid) for 7 days to lower his ammonia level to Conclusion: Untreated homozygous MMA variants, can achieve adulthood with significant renal disease yet their morbidity and mortality can be ameliorated with diet and specific therapy.展开更多
Polycystic kidney disease (PKD) is an autosomal dominant genetic disorder that causes the formation of multiple cysts in the kidneys, leading to kidney failure. PKD is a common condition affecting approximately 1 in 5...Polycystic kidney disease (PKD) is an autosomal dominant genetic disorder that causes the formation of multiple cysts in the kidneys, leading to kidney failure. PKD is a common condition affecting approximately 1 in 500 individuals worldwide. The most prevalent type of PKD is autosomal dominant PKD (ADPKD). ADPKD is caused by mutations in either the PKD1 or PKD2 genes, which encode for proteins involved in cell growth and differentiation. These mutations lead to the formation of fluid-filled cysts in the kidneys, which can eventually lead to kidney failure. In addition to affecting the kidneys, PKD can also cause cysts in other organs, such as the liver, pancreas, and spleen. PKD can also lead to various complications, including high blood pressure, heart valve abnormalities, and brain aneurysms. This review focuses on the inheritance, pathophysiology, and treatment of PKD, with a specific emphasis on its effects on the cardiovascular system. Currently, there is no cure for PKD. However, several treatments are available to manage the symptoms and complications of the disease. These treatments include medications to control blood pressure, pain relievers, antibiotics for infections, and dialysis or kidney transplantation for kidney failure. Tolvaptan is the only FDA-approved drug specifically for ADPKD and has been shown to slow disease progression. In addition to summarizing current treatment options, this review will discuss promising future treatments, such as gene therapy and stem cell therapy.展开更多
Polycystic liver disease(PLD)is a rare hereditary disease that independently exists in isolated PLD,or as an accompanying symptom of autosomal dominant polycystic kidney disease and autosomal recessive polycystic kidn...Polycystic liver disease(PLD)is a rare hereditary disease that independently exists in isolated PLD,or as an accompanying symptom of autosomal dominant polycystic kidney disease and autosomal recessive polycystic kidney disease with complicated mechanisms.PLD currently lacks a unified diagnostic standard.The diagnosis of PLD is usually made when the number of hepatic cysts is more than 20.Gigot classification and Schnelldorfer classification are now commonly used to define severity in PLD.Most PLD patients have no clinical symptoms,and minority with severe complications need treatments.Somatostatin analogues,mammalian target of rapamycin inhibitor,ursodeoxycholic acid and vasopressin-2 receptor antagonist are the potentially effective medical therapies,while cyst aspiration and sclerosis,transcatheter arterial embolization,fenestration,hepatic resection and liver transplantation are the options of invasion therapies.However,the effectiveness of these therapies except liver transplantation are still uncertain.Furthermore,there is no unified strategy to treat PLD between medical centers at present.In order to better understand recent study progresses on PLD for clinical practice and obtain potential directions for future researches,this review mainly focuses on the recent progress in PLD classification,clinical manifestation,diagnosis and treatment.For information,we also provided medical treatment processes of PLD in our medical center.展开更多
AIM To evaluate the novel platelet-derived growth factor receptor and vascular endothelial growth factor receptor dual kinase inhibitor ANG3070 in a polycystic kidney disease-congenital hepatic fibrosis model.METHODS ...AIM To evaluate the novel platelet-derived growth factor receptor and vascular endothelial growth factor receptor dual kinase inhibitor ANG3070 in a polycystic kidney disease-congenital hepatic fibrosis model.METHODS At 6 wk of age, PCK rats were randomized to vehicle or ANG3070 for 4 wk. At 10 wk, 24 h urine and left kidneys were collected and rats were continued on treatment for 4 wk. At 14 wk, 24 h urine was collected, rats were sacrificed, and liver and right kidneys were collected for histological evaluation. For Western blot studies, PCK rats were treated with vehicle or ANG3070 for 7 d and sacrificed approximately 30 min after the last treatments.RESULTS Compared to the wild-type cohort, the PCK kidney(Vehicle cohort) exhibited a marked increase in kidney and liver mass, hepato-renal cystic volume, hepato-renal fibrosis and hepato-renal injury biomarkers. Intervention with ANG3070 in PCK rats decreased kidney weight, reduced renal cystic volume and reduced total kidney hydroxyproline, indicating significantly reduced rental interstitial fibrosis compared to the PCK-Vehicle cohort. ANG3070 treatment also mitigated several markers of kidney injury, including urinary neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, cystatin C and interleukin-18 levels. In addition, this treatment attenuated key indices of renal dysfunction, including proteinuria, albuminuria and serum blood urea nitrogen and creatinine, and significantly improved renal function compared to the PCK-Vehicle cohort. ANG3070 treatment also significantly decreased liver enlargement, hepatic lesions, and liver fibrosis, and mitigated liver dysfunction compared to the PCK-Vehicle cohort.CONCLUSION These results suggest that ANG3070 has the potential to slow disease, and may serve as a bridge toward hepato-renal transplantation in patients with fibropolycystic disease.展开更多
基金Supported by The PKD research program is provided by the Children’s Research Institute,the Lillian Goldman Charitable Trust,Ellsworth FamilyChildren’s Foundation of Children’s Hospital and Health System of Wisconsin
文摘AIMTo investigate the therapeutic potential of tesevatinib （TSV）, a unique multi-kinase inhibitor currently in Phase Ⅱ clinical trials for autosomal dominant polycystic kidney disease （ADPKD）, in well-defined rodent models of autosomal recessive polycystic kidney disease （ARPKD）. METHODSWe administered TSV in daily doses of 7.5 and 15 mg/kg per day by I.P. to the well characterized bpk model of polycystic kidney disease starting at postnatal day（PN） 4 through PN21 to assess efficacy and toxicity in neonatal mice during postnatal development and still undergoing renal maturation. We administered TSV by oral gavage in the same doses to the orthologous PCK model （from PN30 to PN90） to assess effcacy and toxicity in animals where developmental processes are complete. The following parameters were assessed： Body weight, total kidney weight; kidney weight to body weight ratios; and morphometric determination of a cystic index and a measure of hepatic disease. Renal function was assessed by： Serum BUN; creatinine; and a 12 h urinary concentrating ability. Validation of reported targets including the level of angiogenesis and inhibition of angiogenesis （active VEGFR2/KDR） was assessed by Western analysis.RESULTSThis study demonstrates that： （1） in vivo pharmacological inhibition of multiple kinase cascades with TSV reduced phosphorylation of key mediators of cystogenesis： EGFR, ErbB2, c-Src and KDR; and （2） this reduction of kinase activity resulted in signifcant reduction of renal and biliary disease in both bpk and PCK models of ARPKD. The amelioration of disease by TSV was not associated with any apparent toxicity.CONCLUSIONThe data supports the hypothesis that this multi-kinase inhibitor TSV may provide an effective clinical therapy for human ARPKD.
文摘Background Autosomal recessive polycystic kidney disease （ARPKD） is a rare inherited disease, which is a disorder with multiple organ involvement, mainly the kidney and liver. It is caused by mutations in the PKHD1 gene. Here, we reported the clinical characteristics of a case with ARPKD and analyze the genetic features of this patient as well as of his father using targeted exome sequencing and Sanger sequencing. Methods Genomic DNA was extracted from peripheral blood leukocytes obtained from a patient with ARPKD. The mutations were identified using exome sequencing and confirmed by Sanger sequencing. Results The patient was diagnosed as ARPKD based on ultrasonography and abdominal computed tomography which showed polycystic changes, multiple calcinosis of both kidneys, and multiple dilated bile ducts of the liver. Compound heterozygous PKHD1 gene mutations A979G and G5935A, which lead to substitution of an asparagine for an aspartate at amino acid 327 （N327D） and a glycine for an arginine at amino acid 1979 （G1979R） respectively, were identified using targeted exome sequencing and confirmed by Sanger sequencing for the patient. In addition, the father of the patient was identified to be a carrier of heterozygous A979G mutation of this gene. Conclusions We identified that the compound heterozygous PKHD1 gene mutations are the molecular basis of the patient with ARPKD. Targeted exome sequencing is suitable for genetic diagnosis of single-gene inherited diseases like ARPKD in which the pathogenic gene is a large.
基金This project was supported by the National Natural Science Foundation of China(No.81873596).
文摘PKHD1 mutations are generally considered to cause autosomal recessive polycystic kidney disease(ARPKD).ARPKD is a rare disorder and one o f the most severe conditions leading to end-stage renal disease in childhood.With the biallelic deletion mutation,patients have difficulty in surviving the perinatal period,resulting in perinatal or neonatal death.This study retrospectively analyzed patient characteristics,imaging characteristics,laboratory examinations and family surveys from 7 Chinese children with different PKHD1 gene mutations diagnosed by high-throughput sequencing from January 2014 to February 2018.O f the 7 children,there were 3 males and 4 females.Eight missense mutations,two frameshift mutations,two deletion mutations,and two intronic slicing mutations were identified.Six of the mutations have not previously been identified.In the literature search,we identified a total of 29 Chinese children with PKHD1 mutations.The missense mutation c.2507T>C in exon 24 was found in one patient in our study,and five patients with liver fibrosis but normal renal function were reported in the literature.The missense mutation c.5935G>A in exon 37 was found in two patients in our study and three cases in the literature.Four patients had renal failure at an age as young as 1 year of those five patients with the missense mutation c.5935G>A in exon 37.It was concluded that:(1)Kidney length more than 2-3 SDs above the mean and early-onset hypertension might be associated with PKHDI-associated ARPICD;(2)The more enlarged the kidney size is,the lower the renal function is likely to be;(3)c.5935G>A may be a hot spot that leads to early renal failure in Chinese children with PKHD1 mutations;(4)c.2507T>C may be a hot-spot mutation associated with hepatic lesions in Chinese children with PKHD1.
文摘Combined liver-kidney transplantation(CLKT)is a rarely performed complex surgical procedure in children and involves transplantation of kidney and either whole or part of liver donated by the same individual(usually a cadaver)to the same recipient during a single surgical procedure.Most common indications for CLKT in children are autosomal recessive polycystic kidney disease and primary hyperoxaluria type 1.Atypical haemolytic uremic syndrome,methylmalonic academia,and conditions where liver and renal failure co-exists may be indications for CLKT.CLKT is often preferred over sequential liver-kidney transplantation due to immunoprotective effects of transplanted liver on renal allograft;however,liver survival has no significant impact.Since CLKT is a major surgical procedure which involves multiple and complex anastomosis surgeries,acute complications are not uncommon.Bleeding,thrombosis,haemodynamic instability,infections,acute cellular rejections,renal and liver dysfunction are acute complications.The long-term outlook is promising with over 80%5-year survival rates among those children who survive the initial six-month postoperative period.
文摘Background: Methylmalonic aciduria (MMA) is a genetic disorder of aminoacid metabolism, due to mutations in methylmalonyl-CoA mutase, which leads to the accumulation of methylmalonic acid in body fluids. Patients typically present at the age of 1 month to 1 year with dehydration, renal impairment as well as neurologic manifestations viz. seizure, encephalopathy, strokes and disease in the globus pallidi. The case: a 26-year-old man presented with severe acute on top of chronic renal disease with serum creatinine at 590 umol/L and bilateral 8 cm kidneys with thin and echogenic cortex. He had: (a) hypernatremic dehydration, metabolic acidosis and high ammonia level with (b) a history of multiple similar attacks since the age of 8 months. Diagnosis of MMA was confirmed by high serum and urine enzymatic levels as well as genetic testing. His initial management included support with replacements of fluids, electrolytes, and bicarbonates as well as intravenous dextrose, vitamin B12 and broad-spectrum antibiotic (Meropenem) for his chest infection. Subsequently, he received 1) CARBAGLU (carglumic acid) for 7 days to lower his ammonia level to Conclusion: Untreated homozygous MMA variants, can achieve adulthood with significant renal disease yet their morbidity and mortality can be ameliorated with diet and specific therapy.
文摘Polycystic kidney disease (PKD) is an autosomal dominant genetic disorder that causes the formation of multiple cysts in the kidneys, leading to kidney failure. PKD is a common condition affecting approximately 1 in 500 individuals worldwide. The most prevalent type of PKD is autosomal dominant PKD (ADPKD). ADPKD is caused by mutations in either the PKD1 or PKD2 genes, which encode for proteins involved in cell growth and differentiation. These mutations lead to the formation of fluid-filled cysts in the kidneys, which can eventually lead to kidney failure. In addition to affecting the kidneys, PKD can also cause cysts in other organs, such as the liver, pancreas, and spleen. PKD can also lead to various complications, including high blood pressure, heart valve abnormalities, and brain aneurysms. This review focuses on the inheritance, pathophysiology, and treatment of PKD, with a specific emphasis on its effects on the cardiovascular system. Currently, there is no cure for PKD. However, several treatments are available to manage the symptoms and complications of the disease. These treatments include medications to control blood pressure, pain relievers, antibiotics for infections, and dialysis or kidney transplantation for kidney failure. Tolvaptan is the only FDA-approved drug specifically for ADPKD and has been shown to slow disease progression. In addition to summarizing current treatment options, this review will discuss promising future treatments, such as gene therapy and stem cell therapy.
文摘Polycystic liver disease(PLD)is a rare hereditary disease that independently exists in isolated PLD,or as an accompanying symptom of autosomal dominant polycystic kidney disease and autosomal recessive polycystic kidney disease with complicated mechanisms.PLD currently lacks a unified diagnostic standard.The diagnosis of PLD is usually made when the number of hepatic cysts is more than 20.Gigot classification and Schnelldorfer classification are now commonly used to define severity in PLD.Most PLD patients have no clinical symptoms,and minority with severe complications need treatments.Somatostatin analogues,mammalian target of rapamycin inhibitor,ursodeoxycholic acid and vasopressin-2 receptor antagonist are the potentially effective medical therapies,while cyst aspiration and sclerosis,transcatheter arterial embolization,fenestration,hepatic resection and liver transplantation are the options of invasion therapies.However,the effectiveness of these therapies except liver transplantation are still uncertain.Furthermore,there is no unified strategy to treat PLD between medical centers at present.In order to better understand recent study progresses on PLD for clinical practice and obtain potential directions for future researches,this review mainly focuses on the recent progress in PLD classification,clinical manifestation,diagnosis and treatment.For information,we also provided medical treatment processes of PLD in our medical center.
文摘AIM To evaluate the novel platelet-derived growth factor receptor and vascular endothelial growth factor receptor dual kinase inhibitor ANG3070 in a polycystic kidney disease-congenital hepatic fibrosis model.METHODS At 6 wk of age, PCK rats were randomized to vehicle or ANG3070 for 4 wk. At 10 wk, 24 h urine and left kidneys were collected and rats were continued on treatment for 4 wk. At 14 wk, 24 h urine was collected, rats were sacrificed, and liver and right kidneys were collected for histological evaluation. For Western blot studies, PCK rats were treated with vehicle or ANG3070 for 7 d and sacrificed approximately 30 min after the last treatments.RESULTS Compared to the wild-type cohort, the PCK kidney(Vehicle cohort) exhibited a marked increase in kidney and liver mass, hepato-renal cystic volume, hepato-renal fibrosis and hepato-renal injury biomarkers. Intervention with ANG3070 in PCK rats decreased kidney weight, reduced renal cystic volume and reduced total kidney hydroxyproline, indicating significantly reduced rental interstitial fibrosis compared to the PCK-Vehicle cohort. ANG3070 treatment also mitigated several markers of kidney injury, including urinary neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, cystatin C and interleukin-18 levels. In addition, this treatment attenuated key indices of renal dysfunction, including proteinuria, albuminuria and serum blood urea nitrogen and creatinine, and significantly improved renal function compared to the PCK-Vehicle cohort. ANG3070 treatment also significantly decreased liver enlargement, hepatic lesions, and liver fibrosis, and mitigated liver dysfunction compared to the PCK-Vehicle cohort.CONCLUSION These results suggest that ANG3070 has the potential to slow disease, and may serve as a bridge toward hepato-renal transplantation in patients with fibropolycystic disease.
