Involvement of the bone morphogenic protein/SMAD signaling pathway in the etiology of congenital anomalies of the kidney and urinary tract accompanied by cryptorchidism

Background

Congenital anomalies of the kidney and urinary tract (CAKUT), such as renal dysplasia, hydronephrosis, or vesicoureteral reflux, are the most common causes of end-stage renal disease. However, the genetic etiology of CAKUT remains unclear. In this study, we performed whole exome sequencing (WES) to elucidate the genetic etiology of symptomatic CAKUT and CAKUT accompanied by cryptorchidism.

Methods

Three patients with unilateral renal dysplasia accompanied by ipsilateral cryptorchidism were included in this analysis. Genomic DNA was extracted from peripheral blood, and WES was performed. Disease-specific single nucleotide polymorphisms (SNPs) were determined by comparison with the human genome reference sequence (hg19). Additionally, we searched for SNPs that were common to all three patients, with a particular focus on the coding regions of the target genes.

Results

In total, 8710 SNPs were detected. Of the genes harboring these SNPs, 32 associated with renal or testicular development were selected for further analyses. Of these, eight genes (i.e., SMAD4, ITGA8, GRIP1, FREM1, FREM2, TNXB, BMP8B, and SALL1) carried a single amino acid substitution that was common to all three patients. In particular, SNPs in SMAD4 (His290Pro and His291Pro) have not been reported previously in patients with symptomatic CAKUT. Of the candidate genes, four genes (i.e., ITGA8, GRIP1, FREM1, and FREM2) were Fraser syndrome-related genes, encoding proteins that functionally converged on the glial cell-derived neurotrophic factor/RET/bone morphogenic protein (BMP) signaling pathways. As another candidate gene, the protein encoded by BMP8B activates the nuclear translocation of SMAD4, which regulates the expression of genes associated with the differentiation of primordial germ cells or testicular development. Additionally, BMP4, a member of the BMP family, regulates the interaction between metanephric mesenchyme and ureteric buds by suppressing GDNF.

Conclusions

Taken together, our findings suggested that the development of the kidney and urinary tract is intimately linked with that of male reproductive organs via BMP/SMAD signaling pathways.

     

Renal oncocytoma with bilateral synchronous renal cell carcinoma in a patient undergoing long-term hemodialysis

Abstract:   We report a case of bilateral synchronous renal cell carcinoma and renal oncocytoma in a 56-year-old male who had been treated with hemodialysis for 32 years. Because anemia gradually worsened, computed tomography and magnetic resonance imaging were carried out and revealed bilateral renal tumors within acquired cystic disease of the kidney. Bilateral nephrectomy was carried out, and the patient was diagnosed with multiple renal cell carcinomas and a single renal oncocytoma. To our knowledge, this is the first reported case of renal oncocytoma with synchronous renal cell carcinoma in a patient undergoing long-term hemodialysis.     

Correction to: Clinical guidelines for primary sclerosing cholangitis 2017

Journal of Gastroenterology - The article “Clinical guidelines for primary sclerosing cholangitis 2017”, written by Hiroyuki Isayama, Susumu Tazuma, Norihiro Kokudo, Atsushi Tanaka,...     

Acute obstructive suppurative pancreatic ductitis (AOSPD) in pancreatic cancer treated by nasopancreatic drainage

An 80-year-old woman with pancreatic cancer was admitted with fever and abdominal pain. Blood examinations showed an elevated CRP level. On computed tomography (CT), a pancreatic tumor with a dilated upstream main pancreatic duct (MPD) was seen. Endoscopic retrograde cholangiopancreatography (ERCP) showed the strictured part of the MPD at the head of the pancreas with upstream dilatation. A nasopancreatic drainage tube was placed. Through the tube, purulent pancreatic juice was discharged and culture of the pancreatic juice grew Klebsiella pneumoniae. On the day after ERCP, the patient’s condition and the laboratory results improved. The patient’s disorder was diagnosed as acute obstructive suppurative pancreatitis with pancreatic cancer.     

Classification of choledochocele

BACKGROUND/AIMS: Choledochocele is a rare abnormality of cystic or diverticular dilatation of the terminal intramural portion of the common bile duct. Because its anatomic form does not fit the criteria for pancreaticobiliary maljunction, reflux of bile or pancreatic juice has not been discussed in relation to choledochocele. Considering the flow of bile and pancreatic juice, the authors developed a new classification of choledochocele, and investigated associated pancreaticobiliary diseases. METHODOLOGY: We reviewed 82 cases of choledochocele, and classified them into three groups on cholangiopancreatographic findings; Type A (n=27): cystic dilatation of the common channel, Type B (n=31): cystic dilatation of the intramural bile duct forming the common channel, Type C (n=24): cystic dilatation of the intramural bile duct opening into the duodenum separately from the pancreatic duct. RESULTS: Biliary carcinoma was associated with 2 cases of Type A and 1 case of Type B choledochocele. Acute pancreatitis occurred in 10 Type A and 6 Type B choledochoceles. Biliary pancreatic reflux was reported in 4 cases of Type A and 1 case of Type B. Marked elevation of amylase in the bile was reported in 5 Type A and 5 Type B choledochoceles. CONCLUSIONS: In choledochoceles forming a common channel (Type A and B), two-way regurgitation may occur, and induce acute pancreatitis and biliary carcinoma. This classification of choledochocele is useful for analysis of pathophysiology and determination of therapeutic strategy.     

Pancreatic tumor associated with pancreas divisum

BACKGROUND: Although there has been considerable controversy regarding pancreas divisum and pancreatitis, little discussion of this has taken place. The purpose of the present paper was to investigate the relationship between these two conditions. METHODS: A retrospective investigation was undertaken of pancreatic tumors associated with pancreas divisum, in 650 cases of pancreatic carcinoma, 80 cases of intraductal papillary mucinous tumor of the pancreas and 32 cases of pancreas divisum. RESULTS: Of these 32 cases, four (12.5%) were associated with pancreatic tumor: pancreatic carcinoma (n = 3) and intraductal papillary mucinous tumor (n = 1). All tumors developed from the dorsal pancreas of pancreas divisum. Periductal and interlobular fibrosis detected in the non-carcinomatous pancreas of the margin of distal pancreatectomy implied that chronic dorsal pancreatitis associated with pancreas divisum preceded carcinoma. CONCLUSIONS: Pancreatic tumors were detected in 12.5% of cases of pancreas divisum. In pancreas divisum, longstanding pancreatic duct obstruction caused by relative stenosis of the minor duodenal papilla might be a factor promoting oncogenesis.     

A case of double-chambered right ventricle associated with an interventricular septal aneurysm in an elderly patient

Double-chambered right ventricle is a congential malformation caused by an anomalous muscle band obstructing the right ventricular outflow tract. Most reported cases of this condition have been diagnosed in infants, or adolescents. We encountered a 61-year-old woman with a double-chambered right ventricle, associated with a large interventricular septal aneurysm, which is a rare complication. The right ventricular obstruction was corrected with surgery.