Sarcomatoid Urothelial Carcinoma Arising in Autosomal Dominant Polycystic Kidney Disease: A Case Report and Literature Review.

Autosomal dominant polycystic kidney disease (ADPKD) may be associated with various epithelial malignancies. The most reported ones are papillary renal cell carcinoma (RCC) and clear cell RCC. Only one noninvasive urothelial carcinoma arising in the renal pelvis has been previously reported in the setting of ADPKD in the English literature. A 52-year-old patient with ADPKD and a history of renal transplant presented with a poorly differentiated sarcomatoid neoplasm in his native left polycystic kidney. A recognizable urothelial or renal cell carcinoma differentiation was not identified in the resected neoplasm microscopically. The initial diagnosis for this specimen was challenging on morphology and immunohistochemistry, but targeted next-generation sequencing provided molecular evidence in support of urothelial origin, indicating a hotspot mutation -124 C > T in the TERT promoter (C228 T) and loss of heterozygosity on chromosomes 9p and 8p. This tumor is unique because, to our knowledge, this is the first report of upper tract sarcomatoid urothelial carcinoma in a patient with ADPKD.

Incidental renal cell carcinoma post bilateral nephrectomy in autosomal dominant polycystic kidney disease.

BACKGROUND: Renal cell carcinoma (RCC) is more common in patients with autosomal dominant polycystic kidney disease (ADPKD) than in the general population. Diagnosing RCC in ADPKD is challenging due to the presence of multiple renal cysts, often leading to delays and difficulties in distinguishing RCC from cyst infection or hemorrhage. AIM: To analyze the prevalence and characterize the clinical features of RCC in patients with ADPKD undergoing simultaneous bilateral native nephrectomy. METHODS: Between May 2017 and April 2024, 19 ADPKD patients undergoing hemodialysis and awaiting kidney transplantation due to end-stage renal disease (ESRD) underwent bilateral nephrectomies in a single center. Parameters such as patient characteristics, intraoperative blood loss, blood transfusion volume, length of hospital stay, and postoperative complications were documented. Pathological findings for RCC were reviewed. RESULTS: A total of 38 kidneys were excised from 19 patients, with a mean age of 56.8 years and an average hemodialysis duration of 84.2 months. Eight patients underwent open nephrectomies, and 11 underwent hand-assisted laparoscopic nephrectomies. RCC was detected in 15.8% of kidneys, affecting 21.1% of patients. Two patients had multifocal RCC in both kidneys. All RCC cases were pT1 stage, with the largest lesion averaging 16.5 mm in diameter. The average operative duration was 120 minutes, with intraoperative blood loss averaging 184.2 mL. Five patients required blood transfusions. Postoperative complications occurred in five patients, with a mean hospital stay of 17.1 days. The mean follow-up period was 28.1 months. CONCLUSION: The prevalence of RCC is higher in patients with ADPKD with ESRD than in those with ESRD alone. Thus, clinicians should be cautious and implement surveillance programs to monitor the development of RCC in patients with ADPKD, particularly those on dialysis.

Spontaneous Bacterial Peritonitis Due to Bacillus licheniformis in an Autosomal Dominant Polycystic Kidney Disease Patient on Peritoneal Dialysis: A Rare Presentation Linked to Avian Exposure.

This case report details a rare instance of Bacillus licheniformis-induced peritonitis in a 43-year-old male diagnosed with autosomal dominant polycystic kidney disease (ADPKD) undergoing peritoneal dialysis (PD). The patient presented with acute onset of severe abdominal pain and fever, prompting a microbiological investigation that revealed Gram-positive bacilli. Initial empirical treatment with ceftazidime and vancomycin was followed by targeted vancomycin therapy upon identification of B. licheniformis. The patient's clinical course showed steady improvement, corroborated by a recent history of avian contact. This case underscores the critical consideration of uncommon pathogens and environmental exposures in managing peritonitis among peritoneal dialysis patients.

A prioritization tool for cilia-associated genes and their in vivo resources unveil new avenues for ciliopathy research.

Defects in ciliary signaling or mutations in proteins that localize to primary cilia lead to a class of human diseases known as ciliopathies. About 10% of mammalian genes encode cilia-associated proteins and a major gap in the cilia research field is prioritizing which genes to study and finding the in vivo vertebrate mutant alleles and reagents available for their study. Here we present a unified resource listing the cilia-associated human genes cross-referenced to available mouse and zebrafish mutant alleles, their associated phenotypes as well as expression data in kidney and functional data for vertebrate Hedgehog signaling. This resource empowers researchers to easily sort and filter genes based on their own expertise and priorities, cross-reference with newly-generated -omics datasets, and quickly find in vivo resources and phenotypes associated with a gene of interest.

Preclinical Detection of Early Glomerular Injury in Children with Kidney Diseases-Independently of Usual Markers of Kidney Impairment and Inflammation.

Glomerular kidney diseases typically begin insidiously and can progress to end stage kidney failure. Early onset of therapy can slow down disease progression. Early diagnosis is required to ensure such timely therapy. The goal of our study was to evaluate protein biomarkers (BMs) for common nephropathies that have been described for children with Alport syndrome. Nineteen candidate BMs were determined by commercial ELISA in children with congenital anomalies of the kidneys and urogenital tract, inflammatory kidney injury, or diabetes mellitus. It is particularly essential to search for kidney disease BMs in children because they are a crucial target group that likely exhibits early disease stages and in which misleading diseases unrelated to the kidney are rare. Only minor differences in blood between affected individuals and controls were found. However, in urine, several biomarker candidates alone or in combination seemed to be promising indicators of renal injury in early disease stages. The BMs of highest sensitivity and specificity were collagen type XIII, hyaluronan-binding protein 2, and complement C4-binding protein. These proteins are unrelated to inflammation markers or to risk factors for and signs of renal failure. In conclusion, our study evaluated several strong candidates for screening for early stages of kidney diseases and can help to establish early nephroprotective regimens.

[Autosomal recessive polycystic kidney disease in a girl]. / å¸¸æŸ“è‰²ä½“éšæ€§é—ä¼ æ€§å¤šå›Šè‚¾1例.

A 5-year-old girl was admitted due to one episode of melena and one episode of hematemesis. Upon admission, gastroscopy revealed esophageal and gastric varices. Abdominal CT scan, MRI, and color Doppler ultrasound suggested cirrhosis, intrahepatic bile duct dilation, and bilateral kidney enlargement. Genetic testing identified compound heterozygous mutations in the PKHD1 gene: c.2264C>T (p.Pro755Leu) and c.1886T>C (p.Val629Ala). The c.2264C>T (p.Pro755Leu) mutation is a known pathogenic variant with previous reports, while c.1886T>C (p.Val629Ala) is a novel mutation predicted to have pathogenic potential according to Mutation Taster and PolyPhen2. The child was diagnosed with autosomal recessive polycystic kidney disease. In children presenting with gastrointestinal bleeding without obvious causes, particularly those with liver or kidney disease, consideration should be given to the possibility of autosomal recessive polycystic kidney disease, and genetic testing should be conducted for definitive diagnosis when necessary.

Diseases of the primary cilia: a clinical characteristics review.

Ciliopathies encompass a broad spectrum of diseases stemming from dysfunction of the primary (non-motile) cilia, present on almost all cells in the human body. These disorders include autosomal dominant and recessive polycystic kidney diseases, nephronophthisis, and multisystem ciliopathies such as Joubert, Meckel, Bardet-Biedl, Alström, oral-facial-digital syndromes, and skeletal ciliopathies. The majority of these ciliopathies are associated with fibrocystic kidney disease resulting in progressive kidney dysfunction. In addition, many ciliopathies are associated with extra-renal manifestations including congenital hepatic fibrosis, retinal dystrophy, obesity, and brain and skeletal anomalies. The diagnoses may be challenging due to their overlapping clinical features and molecular heterogeneity. To date, over 190 genes encoding proteins that localize to the primary cilia have been identified as disease-causing. This review will discuss the clinical features of the most frequently encountered disorders of primary cilia.

The Influence of Non-Pharmacological and Pharmacological Interventions on the Course of Autosomal Dominant Polycystic Kidney Disease.

Polycystic kidney disease (PKD) includes autosomal dominant (ADPKD) and autosomal recessive (ARPKD) forms, both of which are primary genetic causes of kidney disease in adults and children. ADPKD is the most common hereditary kidney disease, with a prevalence of 329 cases per million in Europe. This condition accounts for 5-15% of end-stage chronic kidney disease (ESKD) cases, and in developed countries such as Poland, 8-10% of all dialysis patients have ESKD due to ADPKD. The disease is caused by mutations in the PKD1 and PKD2 genes, with PKD1 mutations responsible for 85% of cases, leading to a more aggressive disease course. Recent research suggests that ADPKD involves a metabolic defect contributing to cystic epithelial proliferation and cyst growth. Aim: This review explores the interplay between metabolism, obesity, and ADPKD, discussing dietary and pharmacological strategies that target these metabolic abnormalities to slow disease progression. Conclusion: Metabolic reprogramming therapies, including GLP-1 analogs and dual agonists of GIP/GLP-1 or glucagon/GLP-1 receptors, show promise, though further research is needed to understand their potential in ADPKD treatment fully.

Determinants of Disease Progression in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: Despite its severity, there has been a lack of adequate study on autosomal dominant polycystic kidney disease (ADPKD) in Ethiopia. This study assessed the clinical profile and determinant factors contributing to renal disease progression. METHODS: A retrospective study was conducted on 114 patients for 6 years in Addis Ababa. Patients with ADPKD who had follow-up visits at two health centers were included. RESULTS: The mean age at diagnosis was 42.7 ± 12.7 years, with 43% reporting a positive family history of ADPKD. Approximately 22 patients (20%) developed end-stage renal disease, and 12 patients died. The mean estimated glomerular filtration rate at the initial visit was 72.4 mL/min/1.73 m2. The key risk factors associated with disease progression included younger age at diagnosis [adjusted Odds Ratio (aOR): 0.92, 95% CI: 0.87-0.98; p = 0.007], male gender (aOR: 4.5, 95% CI: 1.3-15.95, p = 0.017), higher baseline systolic blood pressure (aOR: 1.05, 95% CI: 1.01-1.10, p = 0.026), and the presence of comorbidities (aOR: 3.95, 95% CI: 1.10-14.33, p = 0.037). The progression of renal disease in ADPKD patients significantly correlates with age at diagnosis, gender, presence of comorbidities, and higher baseline systolic blood pressure. CONCLUSIONS: These findings underscore the importance of early detection and management of hypertension and comorbidities in ADPKD patients to mitigate disease progression and improve treatment outcomes.

Association of hyperphosphatemia with renal prognosis in patients with autosomal dominant polycystic kidney disease.

BACKGROUND: Serum phosphate (P) levels are generally lower in autosomal dominant polycystic kidney disease (ADPKD) than in other kidney disorders, potentially masking the clinical significance of hyperphosphatemia. This study aimed to determine if serum P levels can predict renal outcomes in ADPKD patients. METHODS: We included 235 patients with ADPKD who were not taking drugs to treat hyperphosphatemia. Survival analysis was performed for the renal outcome of a 50% reduction in estimated glomerular filtration rate or initiation of renal replacement therapy. RESULTS: Multivariable Cox regression analyses revealed that serum P (1 mg/dL increase, HR = 2.03, P < 0.0001) was a significant risk factor for kidney disease progression. Similarly, hyperphosphatemia (P > 3.5 mg/dL, HR = 2.05; P > 4.0 mg/dL, HR = 1.90; P > 4.5 mg/dL, HR = 2.78; P > 5.0 mg/dL, HR = 27.22) was significantly associated with renal prognosis. Kaplan-Meier analysis showed significantly lower kidney survival rates in patients with P > 3.5 mg/dL than in those without hyperphosphatemia (log-rank test, P < 0.0001), and similar Kaplan-Meier analysis results were found for P > 4.0 mg/dL, P > 4.5 mg/dL, and P > 5.0 mg/dL. The 2 year kidney survival rate for ADPKD patients with P > 3.5 mg/dL was 66.7% overall and 41.4% in those with stage 4-5 CKD. For patients with P > 4.0 mg/dL, the survival rate dropped to 46.8% overall and 28.2% in those with stage 4-5 CKD, indicating a very poor prognosis. CONCLUSION: Hyperphosphatemia was associated with renal prognosis in patients with ADPKD. In these patients, attention should be paid to even mild serum P elevation of > 3.5 or > 4.0 mg/dL.

Progressive Polycystic Kidney Disease in an Infant Girl With TSC2/PKD1 Contiguous Gene Syndrome.

TSC2/PKD1 contiguous gene syndrome is caused by deletions involving the TSC2 and PKD1 genes that lead to tuberous sclerosis complex and autosomal dominant polycystic kidney disease. It is characterized by early-onset severe cystic kidney disease with progressive enlargement of the kidneys and the cysts. As it can lead to early hypertension and an accelerated decline of kidney function, early genetic testing is needed for early diagnosis of this syndrome, and more frequent imaging-based examinations are necessary to assess disease progression and determine appropriate management. We report the case of an infant girl with TSC2/PKD1 contiguous gene syndrome who presented with epileptic seizures. Brain magnetic resonance imaging (MRI) revealed subependymal nodules and cortical tubers, and abdominal MRI revealed polycystic kidney lesions and enlargement of both kidneys. TSC2/PKD1 contiguous gene syndrome was suspected from her radiological features, and we confirmed the presence of a deletion in the girl's genome, which included the TSC2 and PKD1 genes, via microarray analysis. Thereafter, we evaluated the change in kidney size via repeated abdominal MRI. The polycystic kidney lesions enlarged, and the patient developed hypertension in early childhood, for which we administered an angiotensin-converting enzyme inhibitor. We emphasize the importance of evaluation with longitudinal abdominal imaging because renal cysts tend to enlarge rapidly and induce hypertension, as demonstrated in our case.

Predictors of cerebral microbleeds in patients with autosomal dominant polycystic kidney disease.

OBJECTIVES: Individuals with autosomal dominant polycystic kidney disease (ADPKD) can present with vascular abnormalities, including intracranial aneurysms. However, whether ADPKD is associated with cerebral small-vessel disease, such as cerebral microbleeds (CM), remains unclear. The study analyzes the prevalence of CM and the associated clinical and radiological factors in patients with ADPKD. METHODS: The retrospective study enrolled 140 consecutive patients with ADPKD from July 2014 to May 2023. Brain MRIs were analyzed for the presence of CM with susceptibility-weighted imaging (SWI), which were categorized based on lesion location (lobar, deep, or infratentorial). RESULT: In this study, the prevalence of CM is 26.4%. Chronic kidney disease (CKD) stage (odds ratio [OR]: 1.40, 95% confidence interval [CI]: 1.04-1.88, p = 0.027) and leukoaraiosis grade (OR: 3.29, 95% CI: 1.43-7.56, p = 0.005) were strongly associated with CM. Additionally, both CKD stage (OR: 1.48, 95% CI: 1.06-2.07, p = 0.023) and leukoaraiosis grade (OR: 2.81, 95% CI: 1.30-6.05, p = 0.008) were associated with lobar microbleeds, whereas only leukoaraiosis grade was also related to deep (OR: 9.00, 95% CI: 3.06-26.44, p < 0.001) and infratentorial (OR: 2.48, 95% CI: 1.10-5.61, p = 0.029) microbleeds. The prediction model based on age, CKD stage and leukoaraiosis grade had diagnostic performance with area under curve: 0.804, 0.688, 0.697, respectively. CONCLUSION: We recommend that patients with ADPKD who are aged 58 or older, and who have CKD of at least stage 3, undergo brain MRI for detection of CM.

Importance of IFT140 in Patients with Polycystic Kidney Disease Without a Family History.

Introduction: Recently, the monoallelic loss-of-function IFT140 variant was identified as a causative gene for autosomal dominant polycystic kidney disease (ADPKD). In patients with polycystic kidneys who have a positive family history, >90% have pathogenic variants in PKD1 or PKD2, whereas only 1% have IFT140. However, approximately 40% of patients with polycystic kidneys without a family history do not have any pathogenic variants in PKD1 and PKD2. Methods: We conducted a comprehensive genetic analysis of 157 adult patients with polycystic kidneys whose parents did not have evident polycystic kidneys. We sequenced up to 92 genes associated with inherited cystic kidney disease, including IFT140. Results: Of the 157 patients, 7 (4.5%) presented with monoallelic loss-of-function variants in the IFT140 gene, 51 (32.5%) with pathogenic variants in the PKD1 or PKD2 gene, and 7 (4.5%) with pathogenic variants in other genes related to inherited kidney cystic disease. The proportion of monoallelic loss-of-function IFT140 variants in this cohort was higher than that in previously reported cohorts with polycystic kidneys who had a positive family history. None of the patients with monoallelic loss-of-function IFT140 variants had polycystic liver disease (PLD). Furthermore, patients with IFT140 pathogenic variants had a significantly smaller kidney volume and a remarkably higher estimated glomerular filtration rate (eGFR) than those with PKD1 pathogenic variants (P = 0.01 and 0.03, respectively). Conclusion: Because the phenotype of polycystic kidneys caused by the IFT140 gene is mild, parental kidney disease may be overlooked. Therefore, patients without a positive family history are more likely to carry pathogenic variants in IFT140.

Deficiency of geranylgeranyl biphosphate synthase in kidney tubules causes cystic kidney disease.

Polycystic kidney disease (PKD) is a common hereditary kidney disease. Although PKD occurrence is associated with certain gene mutations, its onset regulatory mechanisms are still not well understood. Here, we first report that the key enzyme geranylgeranyl diphosphate synthase (GGPPS) is specifically expressed in renal tubular epithelial cells of mouse kidneys. We aimed to explore the role of GGPPS in PKD. In this study, we established a Ggppsfl/fl:Cdh16cre mouse model and compared its phenotype with that of wild-type mice. A Ggpps-downregulation HK2 cell model was also used to further determine the role of GGPPS. We found that GGPPS was specifically expressed in renal tubular epithelial cells of mouse kidneys. Its expression also increased with age. Low GGPPS expression was observed in human ADPKD tissues. In the Ggppsfl/fl:Cdh16cre mouse model, Ggpps deletion in renal tubular epithelial cells induced the occurrence and development of renal tubule cystic dilation and caused the death of mice after birth due to abnormal renal function. Enhanced proliferation of cyst-lining epithelial cells was also observed after the knockout of Ggpps. These processes were related to the increased rate of Rheb on membrane/cytoplasm and hyperactivation of mTORC1 signaling. In conclusion, the deficiency of GGPPS in kidney tubules induced the formation of renal cysts. It may play a critical role in PKD pathophysiology. A novel therapeutic strategy could be designed according to this work.

An infant case of autosomal recessive polycystic kidney disease-associated dilated cardiomyopathy-like hypertensive cardiomyopathy diagnosed because of urinary tract infection.

We report a case of dilated cardiomyopathy-like hypertensive cardiomyopathy (HTN-CM) with polycystic kidney disease without family history when a 3-month-old boy developed bacteraemia secondary to a urinary tract infection. He was later confirmed as having autosomal recessive inheritance due to the proven PKHD1 gene mutation. The treatment consisted mainly of antihypertensive and anti-heart failure therapies and he was discharged on the 131st day. To prevent the development of heart failure in patients with HTN-CM due to autosomal recessive polycystic kidney disease (ARPKD), it is important to improve the fetal diagnosis rate of ARPKD, detect hypertension early, and strictly control the blood pressure after birth.

Increasing MicroRNA Abundance by Targeting Biogenesis from the Primary Transcript with Steric-Blocking Antisense Oligonucleotides.

MicroRNAs (miRNAs) are regulators of gene expression, and their dysregulation is linked to cancer and other diseases, making them important therapeutic targets. Several strategies for targeting and modulating miRNA activity are being explored. For example, steric blocking antisense oligonucleotides (ASOs) can reduce miRNA activity by either blocking binding sites on specific mRNAs or base-pairing to the miRNA itself to prevent its interaction with the target mRNAs. ASOs have been less explored as a tool to elevate miRNA levels, which could also be beneficial for treating disease. In this study, using the PKD1/miR-1225 gene locus as an example, where miR-1225 is located within a PKD1 intron, we demonstrate an ASO-based strategy that increases miRNA abundance by enhancing biogenesis from the primary miRNA transcript. Disruptions in PKD1 and miR-1225 are associated with autosomal dominant polycystic kidney disease (ADPKD) and various cancers, respectively, making them important therapeutic targets. We investigated PKD1 sequence variants reported in ADPKD that are located within the sequence shared by miR-1225 and PKD1, and identified one that causes a reduction in miR-1225 without affecting PKD1. We show that this reduction in miR-1225 can be recovered by treatment with a steric-blocking ASO. The ASO-induced increase in miR-1225 correlates with a decrease in the abundance of predicted miR-1225 cellular mRNA targets. This study demonstrates that miRNA abundance can be elevated using ASOs targeted to the primary transcript. This steric-blocking ASO-based approach has broad potential application as a therapeutic strategy for diseases that could be treated by modulating miRNA biogenesis.

Concomitant Wilms tumor and autosomal dominant polycystic kidney disease.

BACKGROUND: Concomitant Wilms tumor (WT) and autosomal dominant polycystic kidney disease (ADPKD) is exceedingly rare, presenting a diagnostic and technical challenge to pediatric surgical oncologists. The simultaneous workup and management of these disease processes are incompletely described. PROCEDURE: We performed a retrospective analysis of patients treated at our institution with concomitant diagnoses of WT and ADPKD. We also review the literature on the underlying biology and management principles of these conditions. RESULTS: We present three diverse cases of concomitant unilateral WT and ADPKD who underwent nephrectomy. One patient had preoperative imaging consistent with ADPKD with confirmatory testing postoperatively, one was found to have contralateral renal cysts intraoperatively with confirmatory imaging post nephrectomy, and one was diagnosed in childhood post nephrectomy. All patients are alive at last follow-up, and the patient with longest follow-up has progressed to end-stage kidney failure requiring transplantation and dialysis in adulthood. All patients underwent germline testing and were found to have no cancer predisposition syndrome or pathogenic or likely pathogenic variants for WT. CONCLUSION: Concomitant inheritance of ADPKD and development of WT are extremely rare, and manifestations of ADPKD may not present until late childhood or adulthood. ADPKD is not a known predisposing condition for WT. When ADPKD diagnosis is made by family history, imaging, and/or genetic testing before WT diagnosis and treatment, the need for extensive preoperative characterization of cystic kidney lesions in children and increased risk of post-nephrectomy kidney failure warrant further discussion of surgical approach and perioperative management strategies.

Retrospective analysis on the occurrence of kidney cysts in mice in a central animal facility in the years 2009-2019.

Kidney cysts in humans are mainly caused by inheritable polycystic kidney disease. Although they are a regular finding in laboratory mice, their occurrence upon dissection has not been systematically investigated, yet. Therefore, the aim of this report was to investigate on prevalence, phenotype and aetiology of spontaneously occurring kidney cysts in mice by retrospectively analysing the laboratory-receipt tables of the in-house laboratory of a central animal facility in North Rhine-Westphalia, Germany, years 2009-2019. A percentage of 0.4% of dissected mice displayed kidney cysts, with more male than female animals affected and average age equal to that of all dissected animals. Preliminary report in half of the cases was distended abdomen, and a few individuals displayed additional pathologic alterations of kidneys, most commonly dilated renal pelvis, or extrarenal comorbidities. Kidney cysts occurred independently of a renal phenotype of the transgenic strain or presence of infectious agents in health monitoring. To conclude, kidney cysts were characterized as harmless for affected mice but, as inheritability is suggested according with the literature, affected animals should be excluded from breeding.