Mechanism of male reproductive failure in autosomal dominant polycystic kidney disease and outcomes of assisted reproductive technology treatment / 上海交通大学学报（医学版）

Objective: To explore the potential mechanism of male reproductive failure in autosomal dominant polycystic kidney disease (ADPKD) patients and analyze the outcomes of assisted reproductive technology treatment. Methods: Next-generation sequencing was performed for genetic diagnosis of 8 ADPKD patients, who came to International Peace Maternity & Child Health Hospital, Shanghai Jiao Tong University School of Medicine, for genetic counseling. The semen of ADPKD patients and normal males who came for pre-pregnancy consultation was collected by masturbation for sperm analysis. The ultrastructure of sperm was observed by transmission electron microscopy. Outcomes of 7 patients with ADPKD who chose preimplantation genetic testing (PGT) were compared with those of 7 patients who were dystrophin (DMD) gene mutation carriers, undergoing the PGT in the same period. Results: Eight patients with ADPKD were heterozygous for polycystin 1 (PKD1) gene. Key parameters of sperm motion including progressive motility sperm percentage, curvilinear velocity, straight-line velocity, average path velocity, amplitude of lateral head displacement were much lower than those of normal semen, showing mild to severe oligozoospermia. One ADPKD patient with severe oligoathenospermia manifested bilateral seminal vesicle cysts. Transmission electron microscopy showed that the central microtubules of the sperm flagella of ADPKD patients were absent and the surrounding double microtubules were disorganized. There was no significant difference in the number of eggs, fertilization rate, cleavage rate, effective embryo rate and excellent embryo rate between the ADPKD patients and the DMD gene mutation carriers, but the ADPKD patients were prone to early abortion. Conclusion: Male reproductive failure caused by ADPKD may be related to many factors such as abnormal structure of sperm flagella and genital cysts. Further, PKD1 mutation may play a role in embryo implantation and early development.

Autosomal Dominant Polycystic Kidney Desease Coexisting with Renal Dysplasia. First Case Described and Followed Since Prenatal Period

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent hereditary renal disease and causes terminal chronic renal failure. ADPKD is characterized by bilateral multiple renal cysts, which are produced by mutations of the PKD1 and PKD2 genes. PKD1 is located on chromosome 16 and encodes a protein that is involved in cell cycle regulation and intracellular calcium transport in epithelial cells and is responsible for 85% of ADPKD cases. Although nine cases of unilateral ADPKD with contralateral kidney agenesis have been reported, there have been no reports of early childhood ADPKD. Here, we report the only case of unilateral ADPKD with contralateral kidney dysplasia in the world in a four year-old girl who was intrauterinely diagnosed since she was 20 weeks old and followed for four years until present.

Esophageal Artery Pseudoaneurysm and Takayasu Arteritis in a Patient with Autosomal Dominant Polycystic Kidney Disease

A 47-year-old female previously diagnosed with ADPKD visited the hospital due to sudden pain in her upper abdomen and back. Esophagogastroduodenoscopy, contrast-enhanced abdominal computed tomography (CT), and CT angiography identified an esophageal artery pseudoaneurysm and hematoma in the esophagus. Urgent angiography and embolization were performed. After the procedure, CT angiography and positron emission tomography were performed due to differences in blood pressure between the arms. The patient was also found to have Takayasu arteritis and subsequently received outpatient follow-up care. The possible mechanisms that cause vascular abnormalities in ADPKD patients include damaged vascular integrity due to abnormal polycystin expression caused by PKD mutations and connective tissue abnormalities. Further research is needed to confirm these mechanisms, and ADPKD patients should be assessed for vascular abnormalities.

Cytokine Profile in the Aspirated Cystic Fluids in Autosomal Dominant Polycystic Kidney Disease (ADPKD) Patients / 대한신장학회잡지

BACKGROUND: The pathogenesis of ADPKD is still unknown but the proliferation of cystic epithelia and the fluid secretion to cystic lumen are thought to be important. Cytokines play a pivotal role in growth, differentiation, and apoptosis in general, but there were few reports about the cytokine profile in ADPKD cysts. METHODS: In this study, we measured cytokine content in aerobic culture-negative cystic fluids from 23 patients with symptomatic normal to end-stage (n=3) ADPKD in order to elucidate the possibility that cytokines are related to the development and progression of disease. Enzyme-linked immunosorbent assays (ELISAs) were used to detect IL-1beta, IL-2, IL-4, IL-6, IL-10, and IFN-gamma with commercial kits. RESULTS: Male to female ratio was 6 : 17 and the median age at examination was 52 years (range 36 to 78). IL-1beta was present in 18 of 23[78%] (11 to 173 pg/mL), IL-2 in 18 of 23[78%] (5 to 159 pg/ mL), IL-4 in 9 0f 23[39%] (8 to 156 pg/mL) and IL-6 in 10 of 23[43%] (16 to 1498 pg/mL). IL-10, and IFN-gamma were not detected. IL-1beta concentrations correlated directly with those of IL-2 (r=0.7671). IL- 6 levels in patients with azotemia (n=7) [288.4+/-26.2 (mean+/-S.D.)] were significantly higher than those of normal renal function group (98.3+/-413.9)(p<0.01). Such difference was not found in other cytokines. Cytokine concentrations did not correlate with sodium concentrations, nor with cystic fluid osmolality, indicating that differences in concentrations among fluids could not be explained by differences in water content. And, there was no significant correlation between the intracystic concentrations of these cytokines and the corresponding cyst diameters. CONCLUSION: These data identify proinflammatory cytokines as possible mediators to the morbidity of ADPKD. Especially, IL-6 levels of cystic fluid were elevated in the azotemic ADPKD patients.

No Association of TGF-beta Gene Polymorphism with the Progression of Autosomal Dominant Polycystic Kidney Disease(ADPKD) in Korean Patients / 대한신장학회잡지

BACKGROUND: Two genetic loci, PKD1 and PKD2, have been identified as being responsible for ADPKD, and PKD1 is known to be associated with poor prognosis. However, the presence of intrafamilial clinical diversity suggests the presence of disease-modifying loci. Because the mechanism of renal failure in ADPKD includes cystic growth and tubulointerstitial atrophy and fibrosis, we studied the associations between two cytokine gene polymorphisms in the TGF-beta gene, which are known to be related with chronic tubulointerstitial inflammation, and ADPKD progression in Korean patients. METHODS: 47 normal controls and 114 individuals with ADPKD were genotyped by PCR-RFLP, and the TGF-beta gene leader sequence of T869C(Leu10Pro) variant was compared with MspA1I and G915C (Arg25Pro) with BglI. Statistic significances were determined using the Chi-square test. RESULTS: The distribution of alleles for the TGF-beta Leu10Pro polymorphism in ADPKD was : T 52%, C 48%, which was similar to the Korean(56 : 44, p= 0.670) and Western controls(65 : 35), and in addition, no differences were found between the CRF and the non-CRF groups(p=0.571) or the early hypertension and the normotension groups(p=0.252). The distribution of alleles for the TGF-beta Arg25Pro polymorphism was all GG type, which was different from Western controls(90 : 10, p=0.000). CONCLUSION: Our results suggest that the polymorphism at Arg25Pro of TGF-beta in Korean population has different allele distribution from Western, and the polymorphism at Leu10Pro of TGF-beta has no association with the renal progression of Korean ADPKD patients.

Cerebrovascular complications in autosomal dominant polycystic kidney disease(ADPKD) / 대한내과학회지

BACKGROUND: ADPKD is one of the most common hereditary renal disease in adult and is a systemic disorder with a variety of cardiovascular manifestations. To elucidate the clinical characteristics of cerebrovascular complications in Korean ADPKD patients, we reviewed the medical records of ADPKD patients who was registered in ADPKD clinic of Seoul National University Hospital. METHODS: A total of 18 adult patients were included and their sex ratio was 8:10. The median age of ADPKD diagnosis was 45.5 year (range 19-85), and age at cerebrovascular accident(CVA) was 52 years(22-82). The median duration from hypertension to CVA was 8 years(0-30). RESULTS: There were 5 cases of infarction, 4 cases of intracerebral hemorrhage, 4 cases of subarachnoid hemorrhage, and 4 cases of transient ischemic attack. Other clinical parameters of ADPKD were not different from patients who were not complicated with CVA. Intracranial aneurysms were detected in 6 patients and their median age at diagnosis was 47.5 years(33-66). Four cases were manifested as subarachnoid hemorrhage. Five cases were diagnosed through TFCA, and two of them were revealed as multiple aneurysms. Five cases received surgical treatment and five of six cases improved without any neurologic sequeale. MR angiography(MRA) were taken in 16 asymptomatic patients, and multiple aneurysms were newly detected in one of them. CONCLUSION: Cerebrovascular complications in Korean ADPKD patients were not significantly different from western patients. Intracranial aneurysms must be included in differential diagnosis in ADPKD patients who manifest an acute neurologic symptoms, and high-risk group need to be screened selectively with MRA.

Genotype Analysis in Korean Families with Autosomal Dominant Polycystic Kidney Disease(ADPKD) / 대한신장학회잡지

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease in adults, and its major morbidities are renal failure and cerebrovascular accident. The prevalence of this disease in the chronic haemodialysis patient population is known to be approximately 2% in Korea. So far, three genetic loci have been identified as being responsible for ADPKD, and approximately 85% of the cases in Western countries are related to the PKD1 gene. However, little information is available concerning the pattern of linkage analysis or the mutations present in Asian populations. For this study, 35 families with hereditary renal cysts were recruited from our ADPKD clinic from 1993 to the present, and their molecular genetic characteristics were studied. Subjects were chosen according to the criteria of Ravine et al. Linkage analysis was done with microsatellite markers(PKD1:SM7, UT581, AC2.5, KG8, D16S418, PKD2 : D4S423, D4S1534, D4S1542, D4S1544, D4S2460). Genomic DNA PCR and PAGE gel run were done, and the allele patterns were compared with sonographic findings. The results of this study showed that the ratio of PKD1 to PKD2 was 23 : 3, and PKD2 families showed the tendency of milder renal prognosis than PKD1 families. In conclusion, we confirmed the usefulness of linkage analysis for ADPKD in Korean population, and our data shows a similar percentage of PKD1(88%) and PKD2(12%) in Korean patients as in the Western population.