Mosaic PKHD1 in Polycystic Kidneys Caused Aberrant Protein Expression in the Mitochondria and Lysosomes

Autosomal recessive polycystic kidney disease (ARPKD) is a severe renal cystic disease caused mainly by the polycystic kidney and hepatic disease 1 (PKHD1). However, the genetic cause, pathologic features, and mechanism of action of ARPKD are not well known. Here, we identified a family with ARPKD. Two siblings harbored biallelic variants in PKHD1 (c.7205G>A, c.7973T>A). We determined that the “de novo” variant, c.7205G>A, arose from the mosaicism of the father and had a 7.4% level. Pathologic characterization, using biopsy analysis, was evidenced with predominant cystic dilation in proximal tubules, slight ectasia of collecting ducts, defective ciliogenesis, and impaired cell-cell junctions in renal tubules and collecting ducts. Exosome proteomics in the urine from patients with ARPKD were markedly different from those of controls, with the most significant alterations occurring in mitochondrial and lysosomal proteins. Expression of the proteins of OXPHOS was downregulated sharply, in parallel with upregulated expression of the proteins involved in glycolysis in patients with ARPKD. Several lysosomal proteins associated with renal lesions were more abundant in the exosome of the patient than in controls. Moreover, the lysosomal enzyme sulfamidase, which is produced by the SGSH gene, was abrupt uniquely in the exosome of the patient. Consistently, swollen mitochondria and abundant lysosomes were visualized in the mutant tubular epithelial cells of patients with mutant PKHD1. Collectively, these findings provide new insights on the pathophysiology of the polycystic kidney due to PKHD1 deficiency. PKHD1 mosaicism should be considered in genetic testing of ARPKD patients.

Cystin genetic variants cause autosomal recessive polycystic kidney disease associated with altered Myc expression

Mutation of the Cys1 gene underlies the renal cystic disease in the Cys1cpk/cpk (cpk) mouse that phenocopies human autosomal recessive polycystic kidney disease (ARPKD). Cystin, the protein product of Cys1, is expressed in the primary apical cilia of renal ductal epithelial cells. In previous studies, we showed that cystin regulates Myc expression via interaction with the tumor suppressor, necdin. Here, we demonstrate rescue of the cpk renal phenotype by kidney-specific expression of a cystin-GFP fusion protein encoded by a transgene integrated into the Rosa26 locus. In addition, we show that expression of the cystin-GFP fusion protein in collecting duct cells down-regulates expression of Myc in cpk kidneys. Finally, we report the first human patient with an ARPKD phenotype due to homozygosity for a deleterious splicing variant in CYS1. These findings suggest that mutations in Cys1/CYS1 cause an ARPKD phenotype in mouse and human, respectively, and that the renal cystic phenotype in the mouse is driven by overexpression of the Myc proto-oncogene.

Renal cystic disease in tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is associated with TSC1 or TSC2 gene mutations resulting in hyperactivation of the mTORC1 pathway. This mTORC1 activation is associated with abnormal tissue development and proliferation such that in the kidney there are both solid tumors and cystic lesions. This review summarizes recent advances in tuberous sclerosis complex nephrology and focuses on the genetics and cell biology of tuberous sclerosis complex renal disease, highlighting a role of extracellular vesicles and the innate immune system in disease pathogenesis.

Smoking accelerates renal cystic disease and worsens cardiac phenotype in Pkd1-deficient mice

Smoking has been associated with renal disease progression in ADPKD but the underlying deleterious mechanisms and whether it specifically worsens the cardiac phenotype remain unknown. To investigate these matters, Pkd1-deficient cystic mice and noncystic littermates were exposed to smoking from conception to 18 weeks of age and, along with nonexposed controls, were analyzed at 13–18 weeks. Renal cystic index and cyst-lining cell proliferation were higher in cystic mice exposed to smoking than nonexposed cystic animals. Smoking increased serum urea nitrogen in cystic and noncystic mice and independently enhanced tubular cell proliferation and apoptosis. Smoking also increased renal fibrosis, however this effect was much higher in cystic than in noncystic animals. Pkd1 deficiency and smoking showed independent and additive effects on reducing renal levels of glutathione. Systolic function and several cardiac structural parameters were also negatively affected by smoking and the Pkd1-deficient status, following independent and additive patterns. Smoking did not increase, however, cardiac apoptosis or fibrosis in cystic and noncystic mice. Notably, smoking promoted a much higher reduction in body weight in Pkd1-deficient than in noncystic animals. Our findings show that smoking aggravated the renal and cardiac phenotypes of Pkd1-deficient cystic mice, suggesting that similar effects may occur in human ADPKD.

MO063DESCRIPTION OF GENETIC VARIANTS IN A COHORT OF TOLVAPTAN ADPKD PATIENTS

Background and Aims Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common inherited renal cystic disease. It is genetically heterogeneous: 72-75% of ADPKD cases are related to mutations in the PKD1, 15-18 % to PKD2 and the remaining 7–10% of affected are genetically unresolved (GUR). Recent years, new drugs have emerged as promising agents that may retard the progression of ADPKD, such as Tolvaptan. In Italy Tolvaptan is available since 2016 and commonly used since 2017 in ADPKD patients, which fulfill the criteria of “rapid disease progression”, according to the European recommendations. High intra-interfamilial variability in pedigrees was observed, despite the same germ-line mutation. This could be explained by other clinical or genetic factors (environmental, modifier genes, etc), that may affect disease severity. The aim of the study is to describe the genetic variants in a cohort of Tolvaptan ADPKD patients (pts) referral to Renal Genetic Disease Ambulatory of Nephrology Department. Method Patients with ADPKD and in Tolvaptan treatment were enrolled. Diagnosis of ADPKD was made upon the revised Ravine’s criteria and Eligibility Criteria for Tolvaptan was made upon Italian indication for Tolvaptan prescription according to Italian Medicine Agency (AIFA) and European Medicines Agency (EMA). We performed genetic analysis (PKD1, PKD2 and PKHD1 genes) to identify mutations by NGS capture-based target enrichment kit (Sophia Genetic™), sequencing on Illumina MySeq Platform® and Sanger Sequencing on 3500 Series Genetic Analyzer (Applied Biosystems™). Results Eighteen pts [median age 46 (IQR 39-48) yrs ], 12 male, were included in the analysis. We manage to perform genetic analysis in all pts. Genetic analysis was essential in 4 patients without family history for Tolvaptan eligibility. Sixteen pts (88,9%) have mutations in PKD1, confirming what is already known from the literature for rapid progressor subjects; 2 pts are characterized by PKD2 mutations, both truncating. In only one pt, concomitant with a PKD1 mutation, also a PKHD1 mutation was found. In order to better characterize the cohort it was decided to subdivide the pts into 3 groups, by gene involvement and mutation type: 1st group: 12 Subjects with truncated PKD1 mutation (66.7%). In 7 pts (58,3%) the mutations are within exons (5 and from exon 11 to 15 inclusive) that encode for Immunoglobulin-like repeats or PKD domain of Polycystin 1 (PC1). 2nd group: 4 Subjects with non-truncated PKD1 mutations (22.2%). 3 pts (75.0%) are characterized by missense variants, as previous studies highlighted (a higher percentage of missense mutations in subjects with non-truncating mutations). In 2 pts (50%) the mutations are within exons (2 and 6) that encode for C-type lectin domain (CTLs) di PC1 and typical domain of extracellular protein. 3rd group: 2 Subjects with a PKD2 mutation (11.1%), both truncating. These data confirmed the lower mutation rate of PKD2 compared to PKD1 and highlighted an effective prevalence of truncation mutations in rapid disease progressors as previous reported. Conclusion Although our cohort of patients is small, we manage to perform genetic analysis in all pts reaching a detection rate of 100%. In 9 of 16 pts (56,3%) with PKD1 mutation the presence of mutations in exons coding PKD domain in PC1 or Immunoglobulin-like repeats or typical domain of extracellular protein allows us to hypothesize that the resulting alteration of the polycystin-mediated cell recognition and communication processes play a crucial role in the pathogenesis of ADPKD.

Prostatic cyst in a pediatric patient with autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inheritable form of renal cystic disease and is associated with cysts in other organs. Prostatic cysts are rare though and have not been reported in the paediatric population. Reported is the presence of a prostatic cyst that was incidentally noted on routine sonogram in a 15 year old with ADPKD.

Renal epithelial and stromal tumor with a multiple cystic lesion localized in the upper portion of the right kidney

A 60-year-old Japanese woman was admitted because of the polycystic mass with right flank pain localized in the upper portion of the right kidney. Right nephrectomy was performed because the mass lesion had continuously increased in size over the past 10 years. A surgical specimen showed histology consistent with a mixed epithelial and stromal tumor, which is closely related to multilocular cystic nephroma, and was diagnosed by a defined capsule between the cystic mass lesion and normal renal tissue by CT and MRI, and histology. Localized renal cystic disease that does not have a capsule was excluded from differential diagnosis.

Unilateral Renal Cystic Disease: A Case Report and Literature Review

BACKGROUND: URCD is a rare disease characterized by cysts with various sizes in a diffusely enlarged kidney without forming a distinct encapsulated mass. We present literature review and report a case of URCD in our center. The aim of the study was to report a case of unilateral renal cystic disease (URCD) in a 25-year-old female. CASE REPORT: The patient was a 25-year-old female. She came to emergency unit of Mitra Medika Amplas Hospital Medan, Indonesia, with dyspepsia associated symptoms. Physical examination and family health-related history were normal. Laboratory examinations and genetic evaluation showed no abnormalities. Ultrasonography examination revealed multiple cysts in her right kidney which was confirmed by computed tomography (CT) scan. The diagnosis of URCD was confirmed. No specific treatment was given and she was advised to do a routine follow-up. CONCLUSION: URCD may present with mild symptoms or even asymptomatic. Diagnosis is confirmed by imaging modalities with normal renal function and absence of genetic predisposition. The management is conservative. Routine follow-up is mandatory.

Complex Renal Cysts (Bosniak ≥ IIF): Outcomes in a Population-Based Cohort Study

There is emerging evidence to suggest that con-current medical conditions influence the outcome of cancers, irrespective of therapy offered. The prevalence and impact of co-morbidities on the survival outcome of complex renal cystic masses in not known. The objective was to study complex renal cysts (Bosniak ≥IIF ) and assess the overall and renal cancer-specific survival in a population-based database including impact of con-current morbidities. The Tayside Urological Cancer Network (TUCAN) database covering a stable population of more than 416,090 inhabitants in a defined geographical area identified 452 complex renal cysts in 415 patients between 2009 and 2019. Each patient was tracked and followed up using a unique identifier and deterministic linkage methodology. The last date of follow-up including cause of death was determined. Co-morbidities were recorded from primary care referrals. Renal cancer-specific mortality was 1.7% at a median follow-up of 76.0 months; however, overall survival was poor, particularly in patients ≥ 70 years of age and with ≥ 2 significant co-morbid conditions (p < 0.0001). A total of 38.3% of the cohort showed con-current morbidities. Age and co-morbidities were significant risk factors for overall survival in patients with complex renal cystic disease and a careful assessment should be made to recommend surgical intervention in the elderly population, in particular in those with other health-related conditions.